FERTIUTY AND STERILITY
I, July 1979
Copyright © 1979 The American Fertility Society
ORAL CONTRACEPTIVES AND NEOPLASIA
GEORGE R. HUGGINS, M.D.
ROBERT L. GIUNTOU, M.D.
Division of Human Reproduction and Division of Oncology,
Department of Obstetrics and Gynecology, University of Pennsylvania
School of Medicine, Philadelphia, Pennsylvania 19104
Combined estrogen-progestogen oral contracep-
tives have been available in the United States
since 1960. The first compound approved con-
tained 10 mg of norethynodrel and 150 145 ofmes-
tranol. Current estimates of worldwide use range
from 54 million to over 80 million and in the
United States use is estimated at 8 million to over
10 million women. 1 Clearly, to justify such wide
use of potent drugs, the risk-benefit ratio must
weigh substantially in favor of the drug benefits.
In the past 19 years over 30 brands of combined
oral contraceptives have been sold in the United
States. Today, they contain one of five synthetic
progestogens (all derived from 19-nortestosterone)
and one of two estrogens. 2 Most women are now
using combined oral contraceptives with 0.3 to 1
mg of progestogen and 20 to 50 145 of estrogen.
Since 1970 all of the newly introduced com-
pounds have used ethinylestradiol as the estrogen
fraction, and all but one have used norethindrone
as the progestogen. One compound contains 0.3 mg
of norgestrel,3 Outside the United States some of
the 17 a-hydroxyprogesterone derivatives are in
use. 3 However, these derivatives were withdrawn
from the United States market in response to con-
cerns regarding the occurrence of neoplastic le-
sions in dogs.
Few issues evoke as much concern and con-
troversy as does the suspected association between
oral contraceptive use and the development of
cancer. Isolated case reports and preliminary
findings may give rise to overwhelming pressure
to discontinue use of the drug with little attempt to
weigh its possible risk-benefit ratios. This re-
sponse is not confined to human evidence. Suspi-
cion of carcinogenicity in any animal species has
raised similar concerns and evoked the same de-
mand for drug withdrawal,4
1
Vol. 32, No.
Printed in U.8A.
Other serious side effects such as cardiovascular
problems with use of the oral contraceptives and
severe pelvic infections with use of intrauterine
devices have extensive documentation. Morbidity
and mortality rates have been estimated. 5-7 By and
large the response of the public and the medical
profession has been to evaluate the risk-benefit
ratio of contraceptive therapy as related to un-
planned pregnancy or induced abortion and to ac-
cept the much lower risk of these very effective
methods of contraception.
We will survey some of the available data and
attempt to evaluate possible associations between
oral contraceptives and human neoplasia in light
of pregnancy risk or benefit of oral contraception.
PROBLEMS OF INVESTIGATION
This investigation is confounded by several
problems: (1) there is no suitable animal model in
most cases; (2) there is generally a long lag-time,
approximately 15 years following exposure to a
carcinogen until the development of overt malig-
nancy8; (3) there is a low incidence of malignant
disease in the young female population; and (4)
there are multiple etiologic influences such as ge-
netic, cultural, geographic, and environmental
exposure to many possible carcinogens.
Each steroid formulation used for contraception
undergoes extensive testing in several animal
species prior to human investigative use. These
animal studies provide only presumptive evidence
of carcinogenic potential within a single species
and sometimes a single strain within the
species. 8-12 Extrapolation of conclusions from one
species to another has dubious validity. Neither
positive nor negative results with animal exposure
to suspected carcinogens can be used with any
2 HUGGINS AND GIUNTOLI July 1979

degree of certainty in relation to the human. The Case Reports

reader is referred to the George Washington Uni-
versity Center Population Reports, 6 which provide
an extensive review of animal studies with sex
steroids and their relationship to benign or malig-
nant neoplasia. Animal studies are not discussed
in detail in this paper.
The relationship of oral contraceptives to benign
neoplasms is germane because some benign neo-
plastic lesions may predispose or progress to frank
invasive cancer. This is especially true with
dysplasia of the cervix, hyperplasia of the endome-
trium, and, to some extent, benign dysplastic
breast disease.
INVESTIGATIVE METHODS
The principal investigative methods in humans
include various epidemiologic approaches 6 (Table
1). The methodologies most frequently used are (1)
case reports (tumor registries), (2) disease rates
and trends, (3) case-control studies, and (4) cohort
studies. Each of these approaches provides a
specific piece of a very complex puzzle. None of
these methods taken by themselves will provide a
definitive answer as to causal relationships be-
tween exposure to an environmental carcinogen
and the occurrence of disease. Needless to say, one
would be unrealistic to ignore increasing and con-
sistent evidence which is confirmed by these mul-
tiple approaches.
The case report (registry) method has served
well to alert us to the appearance of new and
hitherto unsuspected disease entities. In 1971
Herbst et al. I3 first reported the occurrence of vag-
inal adenosis and adenocarcinoma in daughters
born to women who had taken diethylstilbestrol
during early gestation. More recently, Baum et
al. I4 reported the occurrence of benign liver tumors
in oral contraceptive users. These initial reports
provided the impetus for retrospective case-control
and prospective cohort studies. As a result of these
efforts, the association of maternal diethylstilbes-
trol ingestion, adenosis, and adenocarcinoma of
the vagina in offspring is well established. The
question ofliver tumors in oral contraceptive users
is currently under intensive investigation. No con-
clusions regarding either the incidence of disease
or risk of developing the disease can be determined
by using only case reports or surveys.
Disease Rates and Trends
Disease rates for specific malignancies are
available for a number of differing populations. IS
Their incidence varies widely according to geo-
graphic location and other subgroups (Table 2).
Care must be taken not to extrapolate data to other
(dissimilar) populations. This particular approach
has been of limited usefulness in evaluating the
influence of any single etiologic factor on the de-

TABLE 1. Four Epidemiologic Methods Used in Studying Oral Contraceptives and Neoplasia'
Method Description Functions Limitations

Case reports Describe patients, their ill- Often the source of first sus- Few conclusions are made
nesses, and exposures to en- picions about disease causes; on the basis of case reports
vironmental factors; dis- encourage more rigorous alone
cuss suspected interre- study
lationships
Disease rate trends Examine the incidence or mor- Can be compared with trends To produce detectable changes in
tality of a disease in a largein exposure to environmental rates, exposure to environ-
popUlation factors; help assess impact mental factor must be wide-
of disease on public spread in the population and
health must alter the chances of de-
veloping the disease consid-
erably
Case-comparison studies Compare exposure to environ- Determine relative differences Do not determine the incidence
mental factor in groups with in exposure between those rate in either group; depend
a disease with that in simi- with and those without a dis- on records of participants,
lar groups without the dis- ease; appropriate when the which may be faulty
ease disease is rare or quick re-
sults are desired
Cohort studies Compare disease incidence in Appropriate when fullest infor- Often require study of large
groups exposed to an environ- mation, least subject to un- groups over long periods of
mental factor with that in avoidable possibilities of time, especially with rare
groups not exposed methodologic bias, is diseases
required or when information
on more than one disease
is sought
Vol. 32, No.1 ORAL CONTRACEPrIVES AND NEOPLASIA
TABLE 2. Reported Annual Incidence of Cancers of Selected Sites/100,000 Women in Selected Countries, 1960s and 1970s 15
Site of cancer
Nigeria United States
Breast 5.8 89.9
Uterine cervix 7.0 11.4
Uterine corpus 0.5 22.4
Ovarya 3.0 15.5
aIncludes tube.
velopment or progression of cancer. It will, how-
ever, monitor dramatic changes such as those
which have taken place with regard to the increas-
ing incidence of carcinoma of the lung in women. 16
Female Breast Cancer
The data for the United States show little
change over the years for white females, although
information from cancer registries implies a re-
cent increase in older women. The incidence rates
in black women appears to be increasing
significantly.7, 16 Subpopulation groups may show
more marked changes in disease rates, such as the
apparent increasing rate of carcinoma of the
breast in Marin County, California (1960--1973),11
Cancer of the Uterus
Cervix. In New York and Connecticut the trend
for invasive cancer of the cervix shows a steady
decrease in the age-adjusted rate for all ages. The
trend for in situ carcinoma of the cervix shows a
steady increase in the age-adjusted rate for all
ages. IS, 19
Corpus. The Third National Cancer Survey20 in-
dicates a modest decline in the rate of incidence of
corpus uteri cancer. This statistic was confirmed
by both the New York and Connecticut regis-
tries. 21
Cancer of the Ovary
The incidence rates for ovarian cancer have re-
mained about the same over the past 20 years. IS
The rates for all ages declined slightly in the Third
National Cancer Survey.20
Case-Control Studies
The main source of useful retrospective informa-
tion regarding the association between contracep-
tive steroid exposure and the risk of neoplasia is
found in the analysis of case-control studies. 22-29
The approach in case-control or case-comparison
studies is to identify patients with the disease to be
studied and to match them carefully with patients
3
Country
Israel India Japan
57.6 11.3 14.1
4.6 14.3 15.2
11.2 0.7 1.3
13.4 2.7 3.0
who are disease-free. Factors such as age, parity,
race, social class, sexual activity, drug use, concur-
rent disease, and elimination of exposure to other
possible carcinogens are most important in assur-
ing that the populations studied are as similar as
possible. The use of oral contraceptives is then
compared for both cases and controls. Failure to
match for one or more variables can lead to major
invalid hypotheses.
The conclusions are usually expressed as rela-
tive risk or risk ratio. This is based upon the ratio
between the incidence of the disease among the
cases and the incidence among the controls. With
this methodology a relative risk value of 1 would
imply neither a positive nor a negative effect of
exposure. A relative risk of <1 implies a negative
association, and > 1 a positive association with
exposure to oral contraceptives. In this type of
study, highly positive relative risk figures may
give rise to unwarranted alarm because the inci-
dence of the disease in the general population is
not defined. Five times relative risk for a disease
with an incidence of 5/1,000 has more important
implications than five times relative risk in a dis-
ease with a baseline incidence of 5/1,000,000. Un-
fortunately, case-comparison studies when re-
ported in both the lay and scientific press may not
clearly delineate the baseline risk. The potential
exists for overestimating the absolute risk to the
patient.
Case-comparison studies are relatively inex-
pensive, can be done quickly, and can be carried
out at single institutions which are able to obtain
necessary numbers of patients with rare or low-
incidence diseases.
Cohort Studies
The prospective cohort study compares the inci-
dence of disease in patients who are exposed to the
suspected environmental factor with other pa-
tients who are not so exposed. Cancer has a low
incidence among women of reproductive age. The
study of possible carcinogenic effects of oral con-
traceptives requires large numbers of patients fol-
lowed over a long period of time in order to gather
4 HUGGINS AND GIUNTOLI July 1979

TABLE 3. Minimal Samples Required To Detect Differences in ORAL CONTRACEPrIVES AND BREAST DISEASE
Disease Rates between Oral Contraceptive (OC) Users and
Controls in Prospective Study 29 Risk Factors in Carcinoma of the Breast
Persons required
Site of No. of years Annual incidence in each group: Several major risk factors for carcinoma of the
cancer after onset rate in COD- incidence 2 times
of study trols/lO,OOO in OC users breast have been identified35 ,36 (Table 5). The
Breast 1 2.2 85,000 marked predisposition for this disease in the
Corpus uteri 1 0.3 600,000 female is attributed largely to the endocrine
Cervix 1 3.1 60,000 influence of estrogen on breast tissue.
Breast 10 7.5 25,000 Breast cancer has occasionally been reported in
Corpus uteri 10 1.3 140,000 males treated with long-term exogenous estrogen
Cervix 10 5.6 35,000 for carcinoma of the prostate37 or in male to female
transsexuals receiving supplemental estrogen. 38
Postmenopausal use of estrogen may significantly
enough information for adequate statistical anal- increase the risk39 of developing carcinoma of the
ysis 23. 24. 26. 28. 29 (Table 3). breast.
The cohort study can define the baseline inci- The genetic predisposition is stronger in
dence of the disease and compare incidence among families with several relatives involved, especially
users and nonusers in a single population. The cost if the disease has been premenopausal and
and logistical problems involved in adequately bilatera1.40-42 In some populations of women with
conducting a contraceptive cohort study has lim- breast cancer, wet type cerumen (earwax) has been
ited their number. At the present time there are found to be twice as common as the dry type. Pet-
four large contraceptive cohort studies in rakis 43 believes that this significance is based on
progress-two in the United States and two in the simple Mendelian inheritance of a specific apo-
United Kingdom. These are referred to repeatedly crine gland type which produces wet rather than
in this survey30-34 (Table 4). dry cerumen. This genetic typing apparently al-
Care must be taken not to extrapolate data to ters the breast apocrine gland tissue, contributing
other (dissimilar) populations. For instance, sub- in some undefined fashion to increased risk of
jects in the population of the Oxford Family Plan- breast cancer.
ning Study32 were white, married, economically The strongly positive relationship with benign
middle class, and 25 to 39 years old at time of breast disease or precancerous mastopathy is most
enrollment in the study. Conclusions regarding important because ofthe high incidence of benign
carcinoma of the breast in this population may breast disease in the general population and the
have little significance for women in India or considerable difficulty in defining which type of
Japan. benign breast neoplasia is "precancerous."44-51

TABLE 4. Cohort Studies of Oral Contraceptive Use: Background Information 34

No. of women at
enrollment Woman-years of observation
Investigator, year, peri- Nature Age range
od of enrollment of study (yr) Current or Nonusersn Current Ex-users Nonusers n Total
ex-users users

Royal College of Practice- 15-49 23,611 22,766 34,875 9,803 42,306 86,984
General Practitioners,3o based
1974 (subjects enrolled
during 1968-1969)

Ory et al.,31 1976 (sub- Population- 25-49 18,646 50,491 -40,368- 109,310 149,678
jects enrolled during based
1970)

Vessey et al.,32 1976 Clinic-based 25-39 9,653 7,379 -31,076- 10,014 55,829
(subjects enrolled dur- (IUD)
ing 1968-1974) 14,739
(diaphragm)

Walnut Creek Contracep- Health plan 18-54 9,103 5,238 -24,344- 13,029 37,373
tive Drug Study,33 membership-
1974 (subjects enrolled based
during 1968-1972)
--------------------

Vol. 32, No.1 ORAL CONTRACEPI'IVES AND NEOPLASIA 5

TABLE 5. Major Risk Factors in Breast Cancer35 has support from the studies of Spratt and Spratt, 53
Risk factor Comparison Rstio Collins et al.,54 and Silvestrimi et al.5 5 This long
Sex Female Male 99:1 latent, or predetection, phase raises our concerns
Age <40 >40 85%:15% over the effects of exogenous steroids on the pre-
Genetic predisposition detected lesion. If the growth of these tumors is
Family history of Yes No 3:1
breast cancer stimulated by oral contraceptive steroids, one pos-
Mother and sister; Yes No 9:1 sible effect would be the appearance of the lesions
bilateral and in younger women, and progression of the lesions,
premonopausal
Wet type cerumen Yes No 2:1 once clearly detected, would be enhanced. There
(earwax) are no firm epidemiologic data at present to sup-
Previous benign breast Yes No 3:1 port these concerns.
disease
Precancerous mas- Yes No 5:1
topathy
Previous cancer of Yes No 5:1 Breast Cancer and Chronic Mastitis
one breast
Parity (reflects early Nulliparous Parous 3:1 Benign breast disease is not a single well-
first parity)
Age at first Late (>34) Early (18) 4:1 defined process. The histologic descriptive ter-
birth minology is sometimes confusing and inconsistent.
Lactation Yes No 1:1 Fibrosis, fibrocystic disease, cystic mastitis,
adenosis, fibroadenoma, hypermetaplastic dis-
ease, and intraductal papillomas are terms used in
Nulliparous women or women who postpone the discussions of benign breast disease. 56 This incon-
birth of a first child until after age 34 also show sistency makes it difficult to compare accurately
increased risk. 36 conclusions from various reports.
The risk of breast cancer is increased in patients
Breast Cancer, Preclinical Phase with chronic cystic mastitis or fibrocystic disease
The duration of preclinical or predetected breast of the breast. 4 4-51 McDivitt et al.57 have shown a
cancer may extend over many years. Gullin0 52 has much higher risk of cancer associated with lesions
estimated this "latent" time on the basis of an having more marked degrees of atypia. Black and
assumed 100 days' doubling time for breast cancer Chabon58 in 1969 proposed a grading system of
cells (Fig. 1). Using this model, the major conclu- progressive and atypical proliferative changes in a
sion to be drawn from this estimate is that the mammary duct system. These duct changes in se-
clinical phase of breast cancer is by far the shortest quence were given numerical ranking as follows:
phase in the natural history of the disease. (1) control, (2) hyperplasia, (3) and (4) atypia, and
Among the problems associated with this model (5) carcinoma in situ. An increased relative risk (5
are the realities that the tumor cells do not grow at times) for developing cancer was shown in atypia
a constant exponential rate and that a significant grades 3 and 4 as compared with grades 1 and 2.
portion of the tumor is composed of stroma rather Kodlin et al. 56 studied 2931 women with at least
than epithelial cells. However, this assumption one benign breast biopsy obtained at the Kaiser-
Permanente Medical Center in Oakland, Calif.,
between 1948 and 1973. These patients were fol-
100 DAYS DOUBLING TIME lowed for an average period of 6.7 years. The inci-
dence of breast cancer in these patients varied
Diameter em 0.5 1 between 2.5 and 21.111000 person-year rate. Ac-
cording to the Black-Chabon atypia scoring sys-
3 4 5 6 7 8 9 10 11 12 13 tem, the risk increased steadily from 2.5 for lesions
~ YEARS OF GROWTH
...
-' 1012 classified as types 1 and 2 and 21.1 for type 5.
...
CJ
0
10'·
1 kg
Kodlin et al. 56 thought that "in general, it ap-
10'
...
II:
CD 10'
pears that looking at the relative risks with re-
~
:::> 10'
1 mm spect to population expectations, histology can
z
identify groups of somewhat higher risk than
20 30 40 epidemiology .... "56-60 Cole 61 suggested that when
NUMBER OF CEll DOUBLINGS using the Black-Chabon grading scale we have the
FIG. 1. Estimation of duration of preclinical or predetected concept of two types of breast disease, one of which
breast cancer. (Reproduced with permission from Gullino. 52 ) is premalignant and one of which is not.
6 HUGGINS AND GIUNTOLI
TABLE 6. Endocrine Factors Influencing Breast Cancer 69
Experimental
Estrogens are co-carcinogens in rodents
Epidemiologic
Women have 100 times the incidence of breast cancer as men
Occurrence after puberty
Longer menstrual life correlates with more breast cancer
No breast cancer in ovarian dysgenesis
Decreased breast cancer after castration
Protection of early pregnancy
Clinical
Endocrine ablation } .. .
.
E n docrme dd't' Induces remISSIOn m breast cancer
a lIves
Estrogen-induced exacerbations in breast cancer
Role of Hormones
The common feature of hormone-responsive
neoplasms in the breast and endometrium is their
origin from tissues that are specific target organs
for the actions of the estrogenic hormones. Various
clinical observations and epidemiologic studies
have suggested a strong association with endo-
crine influences and the incidence or progression of
breast cancer. 35 . 36. 62-66 Data from early animal
work have shown that in certain animal species
estrogens are carcinogenic and increase the
growth of already existing tumors. 67 . 68 Table 6
lists some of these associations.
Lemon et al. 70 reported in 1966 that women with
breast cancer excreted less estriol (E 3) than es-
trone (E 1) or estradiol (E 2). These observations and
the studies by Cole and MacMahon 71 led to the
development of the "estriol hypothesis." Briefly
stated, this theory argues that the less potent es-
trogen (E3) binds to the breast target cells with the
same affinity and in competition with the more
potent estrogens, El and E 2, and acts as an imped-
ing or blocking agent. 72 As the estrogen stimula-
tion of these cells would be diminished, patients
with high E3 levels might be at decreased risk for
developing breast cancer as compared with popu-
lations of women with relatively high El and E2
levels. 73 These impressions were strengthened by
the findings of high E3 levels among Japanese
women (low risk for breast cancer) and low E3
levels in Caucasian women (high risk for breast
cancer). 74. 75
Needless to say, this concept of predisposition to
breast cancer in patients with low estriol levels is
disconcerting when one considers that patients
taking oral contraceptives have low or absent E3
and E J and all of the commercially available com-
bined oral contraceptives in the United States con-
tain either ethinylestradiol or mestranol (the 3-
methyl ether of ethinylestradioD. Leis and co-
July 1979
workers 36 . 76 believe that, even though E2 is a
biologically strong estrogen, it is not as car-
cinogenic as estrone. Serum levels of estradiol in
patients taking 0.5 mgofd-norgestrel and 50 ~of
ethinylestradiol are low and are consistently in
the postmenopausal range. This low level is main-
tained throughout the usual 7 -day pill-free inter-
val for oral contraceptive users.77
A number of studies have subsequently pro-
duced contradicting data for this estriol hypothe-
sis. Hellman et al. 78 and others 79 . 80 found elevated
E 3levels in women with breast cancer. In addition,
Deshpande et al. 81 found that E3 administered or-
ally in patients with breast cancer did not block
the uptake of E 2. Flood et al. 82 found no significant
differences in urinary E3 levels among women
with previously treated breast cancer as compared
with women without breast cancer. Longscope and
Pratt 83 feel that E3 excretory patterns reflect dif-
fering metabolic pathways rather than differing
production rates. After reviewing available
studies, Kirschner 69 stated that "the estriol
hypothesis as initially received is no longer valid
in explaining altered breast cancer risks." How-
ever, Leis 76 feels that the estriol hypothesis is still
valid in defining potential risks for development of
carcinoma of the breast.
Current evidence would lead one to believe that
concern over the role of estrogens in the etiology of
breast carcinoma may be valid with respect to
long-term unopposed estrogen administration, as
in postmenopausal women, but is not applicable to
young patients who use intermittent oral con-
traceptive therapy.
Oral Contraceptives and Benign Breast
Disease
The relationship of combined oral contracep-
tives to benign breast disease seems to be consis-
tently favorable. Most studies30-34. 84-92 have shown
oral contraceptive use to be associated with a sig-
nificantly decreased risk of benign breast neo-
plasia. The cross-sectional study by Janerich et
al. 92 reported no difference in risk (relative risk
1:1). Kelsey et al. 90 found a lower relative risk only
with sequential oral contraceptive users. Nomura
and Comstock93 found no association with oral con-
traceptive use but an increased risk with estrogen
use, especially diethylstilbestrol.
In spite of the nearly unanimous agreement that
oral contraceptives exert a protective effect with
relation to benign breast disease, a number of
questions and problems persist: (1) Does reponse
differ with respect to duration of use? (2) Does
Vol. 32, No.1 ORAL CONTRACEPTIVES AND NEOPLASIA
response differ according to histologic cell type? (3)
Does response differ for various types and dosages
of contraceptive steroids?
Duration of Use
Most studies30-34. 42, 85-87, 93 have documented a
decreased risk with increasing length of oral con-
traceptive use which begins to appear after 2 years
and persists for over 4 years of use. There is no
suggestion in these studies that the risk increases
with longer use. There is some disagreement as to
persistence of this protective effect after use of oral
contraceptives is stopped. Although Ory et al.31
and Fasal and Paffenbarger87 have shown some
persistence of a protective effect, this finding is not
confirmed by most other studies. There is no
suggestion of increased risks of either benign or
malignant disease after stopping contraceptives.
Response by HIstologic Cell Type
Most studies showing diminished risks for de-
veloping benign breast neoplasia during oral con-
traceptive use have not analyzed lesions by his-
tologic type. The studies which have examined
fibrocystic disease and fibroadenoma separately
have reported somewhat inconsistent results. Ory
et al. 31 reported decreased risks for both fibrocystic
disease and fibroadenoma with combined pills.
Kelsey et al,9o showed a decreased risk for sequen-
tial preparations. Sartwell et al. 86 found the de-
creased risk to hold true only for fibrocystic disease
with combined pills.
Livosli et al.,94 using a case-control study, inves-
tigated the risk of developing fibrocystic disease in
oral contraceptive users by applying the Black-
Chabon scoring system. The main purpose of this
study was to determine whether the association
between oral contraceptive use and fibrocystic dis-
ease varied according to the extent of the breast
epithelial atypia. Two hundred and five pre-
menopausal women aged 20 to 44 years with a
diagnosis of fibrocystic disease, admitted to two
hospitals in New Haven, Conn., comprised the case
population. These patients were matched indi-
vidually with surgical patients for, age, marital
status, race, and education. All biopsies were sepa-
rately classified according to the pathologic
criteria of Black-Chabon. 58
The odds ratio for fibrocystic disease among
women who ever used oral contraceptives was de-
termined according to the average ductal-atypia
score. These determinations were carried out for
"ever-users" and for "four year duration users,"
compared with patients who had never used oral
7
contraceptives. The odds ratio for mild degrees of
ductal atypia was less than 1 for both "ever-users"
and "four year users." The odds ratio was 3 for
"ever-users" and 3.2 for "four year users" in pa-
tients who had severe ductal atypia. Thus the de-
creased frequency of fibrocystic disease applied
only to those forms of the disease in which epithe-
lial atypia was minimal or absent. Women with
marked atypia showed no difference in frequency
among long-term users as compared with "never
users." Livosli et al. 94 believe that long-term use of
oral contraceptives protects only against the forms
offibrocystic disease that are not firmly associated
with an increased risk of cancer but not against the
premalignant forms of breast atypia. There was no
suggestion that the use of oral contraceptives was
associated with a higher incidence of the more
advanced grades of atypia.
Oral Contraceptives and Breast Cancer
Benign breast disease represents a significant
risk factor for the ultimate development of car-
cinoma of the breast. The effect of oral contracep-
tives in most benign breast disease seems to be
protective. However, the studies which show a
consistently protective effect on benign disease do
not show the same protective effect for breast
cancer (Table 7).
Most ofthe derived risk ratios are close to unity.
This figure can be interpreted to indicate no evi-
dence of either positive or negative association
between breast cancer and up to 4 years' use of oral
contraceptives. The 1975 case-control study by
Fasal and Paffenbarger87 in which past and pres-
ent oral contraceptive usage in 452 pre-
menopausal women with breast cancer were
analyzed shows a paradoxical risk pattern. A sig-
nificantly higher relative risk was found among
the cancer patients who had used oral contracep-
tives for 2 to 4 years. However, the risk was not
increased for those pa tients who had taken pills for
less than 2 years or for 4 to 8 years. The authors
proposed two possible conclusions: (1) "that the
findings were due simply to chance" or (2) "that
oral contraceptives accelerate the growth rate of
pre-existing subclinical malignant lesions, with
these lesions reaching the level of clinical recogni-
tion only after two years of drug usage and all
being diagnosed within two additional years." A
second group with increased risk were those pa-
tients who had a history of prior breast biopsy and
oral contraceptive usage for 6 or more years. There
was no reported analysis of these prior biopsy
specimens for degree of atypia or specific cell types.
8 HUGGINS AND GIUNTOLI
TABLE 7. Oral Contraceptives and Breast Cancer:
Literature Review
Report Type of Rate
study ratio
Arthes et al. 85 Case-control 0.7
Boston Collaborative Drug Case-control 0.6
Surveillance Program88
Fasal and Paffenbarger 87 Case-control 1.1
Kelsey et al. 8" Case-control 1.35
Vessey et al. 84 Case-control 0.8
Ory et aPI Cohort 0.7
Royal College of General Cohort 1.1
Practitioners3o
Vessey et al. 32 Cohort 0.4
Vessey et al.,84 in a case-control study of 322
breast cancer patients, looked at some of these
similar factors. They found no significant differ-
ence in oral contraceptive use between cases and
controls by length of use, age, parity, or brand of
oral contraceptive.
Kelsey et al.,89 in a case-control study of 95 pre-
menopausal patients with breast cancer, found no
significant association between use of oral con-
traceptives and breast cancer when analyzed for
duration of use, age at first birth, or length of time
since first use.
Spencer et al.,95 in a case-control study of 44
patients with breast cancer and oral contraceptive
use compared with 44 patients with breast cancer
and non-oral contraceptive use, found no differ-
ence in histology, rate, or extent of axillary metas-
tasis. Recurrence was more frequent in nonusers.
The original data from the cohort studies
showed no association with breast cancer. Recent
unpublished data from three cohort studies were
examined by the World Health organization Sci-
entific Group.34 The findings are conflicting, pre-
liminary, and not conclusive. The data from the
Royal College of General Practitioners Study30 and
the Walnut Creek Contraceptive Drug Study33
suggested a slightly increased risk of breast cancer
in women under 35 years of age with "prolonged
oral contraceptive use." Vessey et aP2 found no
increased risk.
Progesterone. There is no suggestion that pro-
gesterone or the 19-nortestosterone derivatives
may function as breast carcinogens. The Royal
College of General Practitioners reported a possi-
ble protective effect from the progestogens in the
oral contraceptive formulations. 30 During the time
of study all of the combined oral contraceptives in
Great Britain contained only 50 p.g of estrogen,
whereas the progestogen content of the pills varied
from 1 to 4 mg. The incidence of benign breast
disease decreased from 9.95/1000 woman-years
July 1979
with compounds containing less than 3 mg of pro-
1
1
gestogen to 3.75/1000 woman-years for compounds
containing more than 4 mg of progestogen. No
attempt was made to categorize the different pro-
gestogens according to potency.
ORAL CONTRACEPTIVES AND LIVER TUMORS
In 1972 Horvath et al. 96 first suggested a possi-
ble association between oral contraceptives and
ultrastructural findings in the well-differentiated
hepatoma. The following year Baum et al. 97 de-
scribed seven women, all oral contraceptive users,
who developed benign hepatic tumors. These le-
sions were reported as benign hepatic adenomas.
The microscopic appearance was similar to the
description by Edmondson98 in the Armed Forces
Institute of Pathology fascicle. These lesions had
increased numbers of uniformly normal or only
slightly atypical hepatic cells which were ar-
ranged in cords. There were no portal tracts or
central veins, and lobular architecture was absent.
All were vascular and had poorly formed bile
ducts. One tumor was pedunculated and encapsu-
lated; the others were separable from normal liver
tissue, but encapsulation was incomplete. All were
solitary.97
Subsequently, a number of reports have ap-
peared indicating an association between oral con-
traceptive usage and occurrence of liver tu-
mors.98-l05 The histopathologic diagnosis has been
variously reported as focal nodular hyperplasia,
adenoma, hamartoma, benign hepatoma, solitary
hyperplastic nodule, and focal cirrhosis.
Reports of these tumors occurring in young
women taking oral contraceptives immediately
engendered grave concern, because prior to 1970
benign liver tumors in young women were encoun-
tered only rarely. Keifer and Scott l06 reviewed the
literature and were able to find fewer than 80 cases
prior to 1970.
Edmondson et al. 107 reported a case-control
study involving 34 case-control pairs in a study of
42 women with liver adenomas. There were no
differences between the cases and control pairs in
age at interview, menarche, first pregnancy, mean
number of pregnancies, frequency of abortion,
miscarriage, or stillbirth. Most of the cases and
controls had been using oral contraceptives (29 of
30 cases and 24 of 34 controls). However, the mean
duration of use was 79.7 months for cases and 37.8
months for controls. This difference is significant
(P < 0.001 by Student's paired t-test). The relative
risk increased dramatically with duration of use,
--------------~--- -------
ORAL CONTRACEPTIVES AND NEOPLASIA
Vol. 32, No.1
particularly after 60 months. All of the patients
described by Edmondson et a1. 107 had been using
mestranol-containing compounds. They suggested
that, because of the demethylation step at the Ca
position, mestranol-containing compounds might
present an increased risk for development of liver
tumors over and above those containing ethinyles-
tradiol.
Subsequent analysis of case reports have con-
tinued to show a majority of patients who had
taken mestranol-containing compounds, but sig-
nificant numbers of these lesions have been re-
ported in patients taking compounds containing
ethinylestradiol. A few patients have ingested
diethylstilbestrol, conjugated equine estrogens,
and progestogen-only compounds. 10o • 101. 103
104. 106. 107
The Hepatic Branch, Armed Forces Institute of
Pathology, and the Family Planning Evaluation
Division, Bureau of Epidemiology, Center for Dis-
ease Control, in 1977 showed an increasing risk
with increased duration of usage 109 (Table 8). Each
of 79 living women who had a hepatic adenoma
was matched with three neighborhood controls in
a case-control study. These groups were similar
with regard to age, race, education, marital status,
and religion. In addition to duration of use, the
study suggests that women 27 years and older who
have used high-hormone pills for 7 years are at
greastest risk for developing hepatocellular
adenoma.
A liver tumor registry was established at the
University of California School of Medicine at Ir-
vine in June 1975. Nissen et a1. 104 reviewed the
literature and the data from the 71 cases at the
Irvine Registry in 1977. This report confirmed ear-
lier experience regarding patterns of usage in that
64.2% of these patients had taken mestranol-
containing compounds for 71% of the time and only
17% had taken ethinylestradiol-containing com-
pounds for 9.6% of the time. Approximately 85% of
the patients had used an oral contraceptive for
more than 4 continuous years. Nissen et al.
pointed out that this preponderance of mestranol-
containing compounds may have been more ap-
parent than real because the mestranol-
containing brands were produced and marketed
TABLE 8. Increased Risk of Hepatocellular Adenoma in
Women with Use of Oral Contraceptivesl!l9
Duration of use (yr) Risk ratio
0--1 1
1-4 9 contraceptive users and true only for benign le-
4-7 120
8 500
----.----~~- ...
9
prior to the availability of ethinylestradiol-con-
taining compounds. Nissen et al. 104 felt that a
statistical analysis was not possible and awaited
further analysis of larger numbers of patients.
Spontaneous rupture of the liver occurred in 18 of
these patients, resulting in 8 deaths.
In 1977 Keifer and Scott106 surveyed the avail-
able literature and reported 138 cases in United
States literature and added their own cases. This
report confirmed the predominant usage of
mestranol-containing compounds. In discussing
the histopathologic diagnosis of these lesions,
Keifer and ScoW06 felt that the specific histologic
type of tumor might have associated significance.
They observed that rupture of the liver did not
occur in women in whom the pathologic diagnosis
was focal nodular hyperplasia. They also noted
that most of the patients with ruptured liver had
adenomas. Patients taking. oral contraceptives
and having adenomas were at increased risk for
rupture as opposed to nonusers: 30 of 69 users as
compared with only 6 of 27 nonusers. Nine women
with a history of oral contraceptive use had car-
cinoma of the liver. There were 11 deaths from
hemorrhage. Of these women who died, three had
malignancies and eight had benign lesions.
In an attempt to determine more carefully the
extent ofthe problem, the National Cancer Advi-
sory Board requested the American College of
Surgeons' Commission on Cancer to conduct a na-
tional survey of the extent of primary benign and
malignant liver tumors. Four hundred and
seventy-seven hospitals in the United States
searched their tumor registries and reported on all
primary benign and malignant liver tumors in
males and females ages 15 to 45 years from 1970 to
1975.
A total of 543 cases were uncovered, 378 in
females and 165 in males. These cases were
analyzed as to histologic type, age distribution,
and contraceptive usage. Table 9 shows the distri-
bution in females by type of tumor and oral con-
traceptive use. lOS Analysis of malignant tumors
revealed that the frequency increased with age.
This finding mirrors the reported distribution in
the general popUlation. However, the frequency of
the benign lesions showed a large peak in the 26- to
30-year age group. This peak corresponds to in-
creased use of oral contraceptives in this age group
(Fig. 2). This large increase for benign lesions in
the 26- to 30-year age group is true only for oral
sions. Vana et al. 10s confirmed the previous reports
of the excess occurrence in patients using mes-
-----------~------- -

10 HUGGINS AND GIUNTOLI July 1979

48

44

40

36

32
/ \
'"'"co
Q) / \
/
"
28
u
'0
'\..
ci
z 24
I ~. -.... Users (n= 138)
20
/
16
/ .... ...•
Nonusers (n = 39)

12
/
8
J
.I
,/Y-
.......
.......
•. ,
.....!'.
. --..-- -_
--..:.:. ..
Use Not Known (n = 35)

....
....-::-.::-.:::........•....
./
4 /' '

15·20 21·25 26-30 31-35 36-40 41-45

Age Group, yr

FIG. 2. Age distribution of females with benign liver tumors by oral con-
traceptive use.

tranol-containing compounds (three to one versus records of patients enrolled in the Royal College of
those using ethinylestradiol-containing com- General Practitioners Oral Contraception Study
pounds). However, Vana et al. found no dose- (116,000 woman-years' exposure in pill takers)
response relationship and no association with du- and the Oxford Family Planning Association
ration of usage. Forty per cent of tumors were follow-up study of women using different methods
diagnosed in women exposed for 5 years or less. of contraception (over 83,000 woman-years' expo-
Hemorrhage was most frequently associated with sure), and no case of benign or malignant liver
adenomas and almost exclusively confined to the tumor was found. In addition, the records of the
oral contraceptive users. Oxford Linkage Study were searched. This study
covers the hospital admissions and deaths in a
Estimated Incidence of Liver Tumors population of more than 1,000,000. No benign liver
tumors were found in women of childbearing age
Vana et al. 10S estimated the incidence of benign
from 1970 through 1975.
tumors at 4.9/1,000,000. This figure agrees with
One case of benign liver tumor was found in a
the estimate of 11500,000 to 111,000,000 by Baum
23-year-old woman taking oral contraceptives for
et aP7 Garcia et al. 110 suggested an incidence at
2 years in a search of the Scottish National Diag-
0.04/100,000 women, and Berg et al. 111 estimated
nostic Index for the years 1968 through 1974. The
the incidence at 0.29/100,000 women. The World
system covers hospital admissions and deaths for a
Health Organization34 suggested an increased in-
population of approximately 5,000,000 people.
cidence of less than 3/100,000 woman-years for
women under the age of 30 and an unknown but Clinical Aspects
greater rate for those over the age of 30.
These low estimates of occurrence rates were Although benign, these tumors may be life-
confirmed by Vessey et al. 112 They searched the threatening because of their tendency to spon-
Vol. 32, No.1 ORAL CONTRACEPTIVES AND NEOPLASIA
taneous hemorrhage with resultant death. The pa-
tient at highest risk for spontaneous hemorrhage
seems to be an oral contraceptive user who has a
large mass of the hepatic cell adenoma histologic
type and who has taken a high-dose combined pill
for more than 4 years.
These lesions can first present themselves as an
asymptomatic mass, but the majority of patients
initially complain of epigastric or right upper-
quadrant abdominal pain. Unfortunately, a
significant number of these patients also present
with signs of intraperitoneal hemorrhage and
shock. Timing may be significant in that some of
these lesions seem most prone to rupture at or
about the time of menstruation. 10o. 104. 106-108
The standard blood liver function tests are of
little value in diagnosing these lesions as no con-
sistent abnormalities are found. Celiac arteriog-
raphy, ultrasonography, and liver scan offer the
most accurate diagnostic approaches. The need for
confirming tissue diagnosis must be weighed
against the risk of hemorrhage due to needle or
open biopsy. These lesions are very vascular, and
biopsy alone is attendant with significant risk. A
number of the reported deaths have occurred sec-
ondary to attempts at resection.
Most of the reported lesions have been managed
aggressively with attempts at complete resection.
There is some preliminary evidence that these
tumors will spontaneously regress after oral con-
traceptives are stopped. 100-102. 113-115 Ory et a1. 109 re-
ported that resumption of oral contraceptive use
may have stimulated a recurrence in 12.5% ofpa-
tients in their series. Pregnancy, with the resul-
tant high levels of sex steroids, may have a par-
ticularly stimulating effect and increase the pro-
pensity for these lesions to hemorrhageY6-120
At present there is no consensus as to the best
method of managing these lesions. For those le-
sions which are asymptomatic the best and safest
course would be to discontinue the oral contracep-
tives, urge the patient to avoid pregnancy, and
await spontaneous resolution of the lesion.
ORAL CONTRACEPTIVES AND
PITUITARY TUMORS
Prolonged secondary amenorrhea after discon-
tinuing oral contraceptive use was first reported
by Shearman121 in 1966. Subsequently, the associ-
ation of postpill amenorrhea, galactorrhea, and
the existence of pituitary tumors was
described. 122-126 Van Campenhout et al. 127 reported
an incidence of 32% pituitary tumors (10 of 31
patients) in women with postpill amenorrhea-
11
galactorrhea, and an incidence of 41% (16 of 39
patients) in women who had non-postpill
amenorrhea-galactorrhea.
March et al,126 analyzed 191 patients with sec-
ondary amenorrhea. In 69 women the amenorrhea
followed discontinuation of oral contraceptive use,
whereas in 122 it was unrelated to oral contracep-
tive use. Tomographic evaluation revealed pitui-
tary tumors in 18 patients (26%) with postpill
amenorrhea and in 16 (13%) of those with non-
postpill amenorrhea. This difference was signifi-
cant (P < 0.001).
An expanded study by March et al. 128 revealed
41 of 75 patients with amenorrhea-galactorrhea
and radiographic evidence of tumor, whereas only
8 of 35 patients with hypothalamic-pituitary fail-
ure without galactorrhea had an abnormal sella.
Davajan et al.,124 from the same institution,
studied patients with galactorrhea and secondary
amenorrhea. Because a reliable history of prior
oral contraceptive use was obtained in only
slightly more than one-half of the patients, they
believed that it was impossible to associate the use
of oral contraceptives with either hyperprolac-
tinemia or abnormal x-ray findings.
Using poly tomography and radioimmunoassay
for prolactin determinations, Kleinberg et al. 122
reported pituitary tumors in approximately 30% of
patients with secondary amenorrhea-galactorrhea
associated with oral contraceptive use. The sub-
clinical incidence of this disease may be quite high.
Costello129 found a 22.5% incidence of asymptoma-
tic and unsuspected pituitary adenomas in 1000
autopsies at the Mayo Clinic. Coulam et al. 130 re-
ported a decreased relative risk (0.5) for pituitary
tumors in oral contraceptive users in a case-
control study from the Mayo Clinic. They con-
cluded that the apparent increased incidence of
pituitary tumors in Olmsted County, Minn., from
1935 through 1977 was probably due to advances
in diagnostic and surgical technology rather than
to a specific etiologic factor. This study involved
only nine patients.
No firm conclusions regarding an association
between pituitary adenoma and oral contraceptive
use are possible with the data available.
ORAL CONTRACEPTIVES AND ENDOMETRIAL HYPERPLASIA
Estrogen and Endometrial Neoplasia
Estrogen may produce endometrial hyperplasia
ifnot interrupted or opposed by progesterone. This
entity has been shown to advance to adenomatous
12 HUGGINS AND GIUNTOIJ July 1979

TABLE 9. Distribution of Benign Liver Tumors a105

Use of oral contraceptives Total
Users Nonusers Not known
Type of tumor
No. % No. % No. % No %

Hepatic cell adenoma 71 51.4 11 28.2 14 40.0 96 45.3

Focal nodular hyper- 43 31.2 8 20.5 7 20.0 58 27.4
plasia
Hamartoma 13 9.4 12 30.8 8 22.9 33 15.6
Other benign 11 8.0 8 20.5 6 17.1 25 11.7

Total 138 100 39 100 35 100 212 100

aDistribution in females by histologic type and use of oral contraceptives.

hyperplasia, carcinoma in situ, or eventually en-
dometrial cancer.131-135 This progression is well
recognized in patients with Stein-Leventhal syn-
drome 136 and with estrogen-producing tumors.137
The administration of exogenous estrogens, both
naturally occurring and synthetic, has been shown
to produce endometrial hyperplasia in women
treated for long periods of time. l38 • 139 Post-meno-
pausal estrogen use has also been associated with
the occurrence of endometrial carcinoma.140-144
A number of case-control studies have linked
endometrial cancer in postmenopausal women to
estrogen use. These studies have shown consistent
and significantly increased relative risks (Table
10). Certain objections and criticisms have been
raised with respect to these studies: (1) Diagnostic
surveillance for women taking estrogens may
have been increased, so that early lesions would be
diagnosed more quickly than lesions in patients
not taking estrogens. (2) It is possible that en-
dometrial hyperplasia may have been mis-
classified as early endometrial carcinoma. More
advanced stages of endometrial neoplasia have not
been studied in adequate numbers. (3) Early cases
of endometrial carcinoma have inadvertently been
treated with estrogens. (4) The history of drug
exposure may have been inadequate. (5) Details of
estrogen use may not have been sufficient.
In 1978 Antunes et a1. 145 conducted a large case-
control study of the relationship between estrogen
use and endometrial cancer. The study was de-
signed to address the above-noted criticisms of
previous work. Four hundred and fifty-one pa-
tients with endometrial carcinoma were identified
(7% stage 0, 70% stage I, and 23% stages II, III, and
IV). These patients were matched with 450 con-
trols. Pathologic slides were independently re-
viewed. Information about drug use by type and
duration was obtained. There was no difference in
time to physician consultation for postmenopausal
bleeding between estrogen users and nonusers. No
patients in this study who had endometrial car-
cinoma had inadvertently been treated with estro-
gens.
The over-all risk of endometrial carcinoma was
6-fold for estrogen users as compared with nonus-
ers. Long-term use over 5 years carried with it a
15-fold risk. Despite the failure of case-control,
epidemiologic studies to prove a causal relation-
ship, the present evidence seems to suggest that
postmenopausal use of estrogens in women with
an intact uterus is associated with an increased
risk of endometrial carcinoma.
Sequential Oral Contraceptives
In 1963, sequential oral contraceptives were
first marketed in the United States. Their use was
prompted in part by an effort to simulate more
clearly the natural sequence of estrogen only fol-
lowed by estrogen-progesterone elaboration as
found during the normal menstrual cycle. The
scheme of administration involved estrogen (80 to
100 p.g) alone for 14 to 16 days followed by an
estrogen-progestogen combination for 5 or 6 days.
The progestogen content varied from 3 to 25
mg. 146. 147
Silverberg and Makowski 148 and Lyon 149 in 1975
first reported the occurrence of endometrial car-
cinoma in young women taking sequential oral
contraceptives. These reports were quickly fol-
lowed by others.150-154 A "registry" for endometrial
carcinoma in young women taking oral contracep-
tive agents was established in Denver in 1973. By
June 1976 the registry had recorded 30 cases of
verified invasive carcinoma of the endometrium
TABLE 10. Association of Estrogen Use and Adenocarcinoma
of the Endometrium: Case-Control Studies
Report and year Relative risk
Smith et al.,t42 1975 7.5
Zeil and Finkle,t43 1975 7.4
Mack et al.,t40 1976 8.0
Gray et al.,t'l 1977 3.1
Antunes et al.,t" 1979 6
Vol. 32, No.1 ORAL CONTRACEPrIVESAND NEOPLASIA
occurring in women under the age of 40 who had a
documented history of oral contraceptive use.
Twenty patients had documented ingestion of se-
quential type preparations, nine had used com-
bined formulations, and one patient had used an
unknown type. Nineteen of the twenty patients
using sequentials had used one preparation con-
taining 100 ILg of ethinylestradiol as the estrogen
and 25 mg of dimethisterone as the progestogen. 150
Because of the lack of a population-based regis-
try, the above authors were unable to establish
whether endometrial carcinoma was more com-
mon in women using sequential agents than in the
general population, or whether the incidence was
merely decreased in users of combined agents.
Further epidemiologic analysis of this problem in
the United States by case-control or cohort studies
was not possible. In 1976, the sequential oral con-
traceptiveswere voluntarily removed from the
market by the manufacturers.155
Progesterone--Endometrial Effects
Progesterone competes with estrogen for bind-
ing sites in the endometrial cells and may reduce
the estrogen-stimulating effect.156, 157 The expo-
sure of the normal estrogen-primed endometrium
to progesterone converts the tissue to the typical
secretory type seen during the luteal phase of the
menstrual cycle. This cyclic effect of progesterone
prevents the normal proliferative endometrium
from progression to hyperplasia. 158, 159
The hormonal milieu of patients taking com-
bined oral contraceptives is quite different from
that seen in patients taking postmenopausal es-
trogens or patients using sequential type oral con-
traceptives. The daily addition to the estrogen of a
potent progestogen produces a markedly altered
endometrial response. This type of endometrium
has a decidual pattern formation with a tendency
to atrophy rather than progress to hyperpla-
sia.160, 161
The ability ofthepotent progestogens to produce
progressive endometrial atrophy has led to sug-
gestions that they be used therapeutical-
ly.159, 162, 163 High doses of progestogens in some
patients have been shown to convert adenomatous
hyperplasia to normal histology.162-164 Wentz 162 in
1974 reported two series of patients with atypical
or adenomatous hyperplasia treated with oral pro-
gestogens. In the first study, 10 patients with atyp-
ical endometrial hyperplasia and 10 patients with
adenomatous hyperplasia were treated with 100
mg of dimethisterone (6a-21-dimethyltestoster-
one) daily for 6 weeks. They were then followed
13
with repeated endometrial samplings. Of the 20
patients, 17 were followed for more than 30
months. Histologic study of the endometrium re-
vealed a return to normal histology in all patients.
. There were no recurrences of hyperplasia. The sec-
ond study involved 80 patients with adenomatous
hyperplasia and 30 patients with atypical
hyperplasia. Treatment involved administration
of 20 mg of megestrol (17a-acetoxy-6-methyl-
pregna-4,6-diene-3,20-dione) orally in four divided
doses daily for 6 weeks. All lesions reverted to
normal histology and there were no observed recur-
rences in 2 years of follow-up.
In addition to their ability to convert adenoma-
tous hyperplasia to normal, pharmacologic doses
of progestogens (medroxyprogesterone acetate,
hydroxyprogesterone caproate, megestrol, med-
rogestone) may be used to treat metastatic
adenocarcinoma of the endometrium. They will
produce objective regression of the lesions in ap-
proximately 30% of patients. 164
The extreme rarity of endometrial carcinoma in
women under age 40 accounts in part for the lack of
any large case-control study ofthe association be-
tween combined oral contraceptive use and en-
dometrial carcinoma. The ongoing cohort
studies 30-33 have not reported on endometrial
cancer, and, unless the incidence of endometrial
carcinoma in women enrolled in these studies in-
creases substantially, this type of study will not
provide enough cases for statistical analysis. Con-
versely, the lack of reports of endometrial cancer
in large populations over many years would be
most reassuring and would suggest a neutral or
negative risk.
Although there is no suggestion in the current
literature that patients taking combined oral con-
traceptives, progestogen-only pills, or injectable
progestogens are at increased risk for developing
hyperplasia or adenocarcinoma of the endome-
trium, further evaluation is needed with case-
control studies and monitoring incidence reports
in the cohort studies.
MYOMAS
Estrogens seem to have an association with
myomas. They rarely occur before menarche and
tend to regress after menopause. They may en-
large rapidly during pregnancy or during exoge-
nous estrogen administration. 165 In the early his-
tory of combined oral contraceptive development,
it was feared tht myomas might grow under the
stimulation of the estrogen contained in the oral
contraceptives. In part, as a result of this concern,
14 HUGGINS AND GIUNTOLI
myomas have been considered a relative contrain-
dication for oral contraceptive administration, and
many physicians are reluctant to use oral con-
traceptives in patients who have a myoma of any
type or size.
At present, there is little objective evidence in
the literature to support this concern. The Royal
College of General Practitioners' cohort study30
found a significantly decreased risk of developing
uterine myomas in users versus nonusers. Vessey
et al,32 found no significant difference in occur-
rence rates. None of the patients in either of these
studies was taking medication with more than 50
jJ-g of estrogen. Because myomas are considered a
relative contraindication to oral contraceptive use,
patients in these cohort studies with pre-existing
myomas may be prevented by their physicians
from taking oral contraceptives. If this does occur,
patients with known myomas could be selectively
assigned to other contraceptive methods and pre-
selection bias could mask analysis of a possible
association between the oral contraceptive and the
occurrence of myomas.
The low-dose estrogen combined oral contracep-
tives used today should present little concern in
patients with asymptomatic uterine leiomyomas.
Should myomas increase in size in patients using
low-dose pills the oral contraceptives ought to be
discontinued.
CERVICAL NEOPLASIA
The epidemiologic factors responsible for the de-
velopment of cervical dysplasia and subsequent
progression to carcinoma in some patients are
complex and poorly understood. One of the major
epidemiologic factors in carcinoma of the cervix
seems to be young age at first intercourse. Others,
such as multiparity, high frequency of intercourse,
multiple partners, and low socioeconomic status,
may also relate to early age at the time of first
intercourse. 166-168
Conclusions derived from a number of
epidemiologic studies of cervical neoplasia vary
considerably. A number of factors contribute to
this variability: (1) The histologicinterpretation of
degrees of dysplasia and carcinoma in situ may
vary from one pathologist to another. (2) The most
important risk factors (age at first intercourse,
frequency of intercourse, and number of sexual
partners) are difficult to determine accurately. In
spite of the large numbers of both case-control and
cohort studies, only one study prior to 1975
specifically analyzed the issues of age at first in ter-
course and contraceptive choice. 168 (3) There is a
July 1979
tendency for women using steroidal contraception
to avail themselves of medical care more fre-
quently than noncontraceptive users. As a result,
certain disease processes may be under-reported in
populations not using contraceptives. (4) Results
are inconsistent in quantitating relative risks.
Some reports conclude that there are "remarkable
similarities between the test and control group in
each age bracket"169 or "no significant differences
in occurrences or duration of use."170 (5) Some re-
ports concern "prevalence rates," which may in-
clude patients with disease at the time they enter
the study. 171 (6) There is a confounding influence of
sexually transmitted carcinogens. Until the possi-
ble carcinogenic potential of herpesvirus and other
infectious processes are better defined, epidemio-
logic studies will be unable to control adequately
for these factors in study design or data analy-
SiS.172-174
Condom and diaphragm use may exert some
barrier protective effect against these agents.
Comparisons between incidence rates of infection
and cervical neoplasia in diaphragm users versus
oral contraceptive users may show a protective
effect of diaphragm use rather than an increased
rate with oral contraceptive use.
Cervical Changes and Oral Contraception
Under the influence of combined oral contracep-
tives the cervix becomes hypertrophic and the en-
docervical canal undergoes eversion. In the nul-
liparous patient this process exposes the endocer-
vical cells to the vaginal environment for the first
time.175 The progestogen component of the oral
contraceptives on occasion produces hypertrophic
adenomatous changes in the endocervical col-
umnar epithelium which are similar to the
changes seen during pregnancy.176-178 These
changes may look bizarre and, on occasion, have
been mistakenly interpreted as malignant.178-184
They are, however, benign and regress after dis-
continuing the progestogens; they do not recur fol-
lowing excision.
Taylor et al. 184 reported on 13 patients in whom a
distinctive type of atypical polypoid endocervical
hyperplasia was found. Twelve patients were tak-
ing oral contraceptives and one patient was being
treated with progestogens for endometriosis. The
lesions grossly resembled a polyp. Histologically
there were areas of atypical patterns which caused
concern as to whether the lesions represented car-
cinoma. Only one of these patients had an abnor-
mal Papanicolaou smear. The patients were all·
treated with multiple biopsies or cervical coniza-
Vol. 32, No.1 ORAL CONTRACEPTIVES AND NEOPLASIA
tion. Histologic study showed no stromal invasion,
and local excision was curative with no recorded
recurrences.
Candy and Abell 180 subsequently described an
additional 12 patients with adenomatous hyper-
plasia of the cervix. Seven of these patients had
been referred to them with a diagnosis of adeno-
carcinoma of the cervix. Eleven of the twelve pa-
tients were using combined oral contraceptives
containing 2 to 5 mg of progestogen and 75 to 100
145 of estrogen. One patient was being treated with
1000 mg/week ofmedroxyprogesterone acetate for
adenocarcinoma of the endometrium. All lesions
were treated by simple excision. The histologic
diagnosis was adenomatous hyperplasia. There
were no recurrences.
Subsequent reports have confirmed these initial
observations.181.184 The histologic changes may
look bizarre and may be mistakenly interpreted as
adenocarcinoma. They are, however, benign and
regress after discontinuing the progestogens. They
do not recur following excision.
Case-Control Studies/Surveys of
Cervical Neoplasia
Worth and Boyes 170 in 1972 conducted a case-
control study of 308 Canadian women with car-
cinoma in situ. Each case was matched with two
controls. No significant differences were noted in
oral contraceptive use or type of formulation be-
tween the group with carcinoma in situ and the
normal controls.
Thomas,185 in another case-control study, re-
viewed 378 white women in Maryland with class
III- V cytology smears. These patients were
matched with 360 patients who had normal
smears. No significant differences were noted for
oral contraceptive use, type of formulation, or du-
ration of use.
In 1973 Miller 186 surveyed cytologic smears
taken on 15,532 women in a predominantly white
(97.8%) population in Connecticut. Of this total,
2,294 oral contraceptive takers were identified and
matched with an equal number of controls. Pa-
tients were matched for age and "same general
length of time" observed. No significant differ-
ences were found in abnormal cytology between
cases and controls.
Boyce et al.187 compared 689 women with car-
cinoma in situ or invasive carcinoma of the cervix
with 689 matched controls and found no increased
relative risk with regard to oral contraceptive use
by type or duration of use and age at first inter-
course.
15
The incidence of cervical carcinoma in situ was
surveyed in 1969 by Melamed et al.,171 who related
epithelial abnormalities to a "matched" popula-
tion of Planned Parenthood patients in New York
City. Five factors were considered in the study
design for collection of clinical data: age, ethnic
origin, age at first pregnancy, number of children
born alive, and net weekly family income. No at-
tempt was made to determine age at first coitus,
frequency of coitus, or number of different sexual
partners and marital status.
Analysis of the "matched populations" of oral
contraceptive choosers and those who selected the
diaphragm revealed significant differences in
race, income, and age at first pregnancy. The dia-
phragm users were predominantly white, of upper
income socioeconomic status, and more likely to
have had their first pregnancy after age 20. The
oral contraceptive choosers were predominantly
black or Puerto Rican, of lower income socioeco-
nomic status, and more likely to have had their
first pregnancy before the age of 20. Prevalence
rates were determined for patients choosing oral
contraceptives (27,508) and patients selecting the
diaphragm (6,809). Prevalence rates for carcinoma
in situ for oral contraceptive choosers was 6.6/
1,000 and 3.8/1,000 for diaphragm users. This dif-
ference was small but statistically significant.
Assuming that this was not a low-probability
statistical variation, three possible explanations
were offered: (1) a protective effect of the dia-
phragm acting as a barrier, (2) a causal effect of
steroids acting on the cervicovaginal epithelium,
and (3) some unknown factor(s) in the makeup,
behavior, or habits of a woman that would alter
her probability of developing cervical carcinoma
and at the same time impel her to choose a particu-
lar contraceptive.
It is important to appreciate that the study by
Melamed et al.l7l demonstrated only a tendency of
patients with carcinoma in situ to choose oral con-
traceptives more frequently than the diaphragm.
No conclusions could be drawn regarding the de-
velopment of carcinoma in situ in patients using
oral contraceptives.
The patients enrolled during the initial study
phase in 1969 were subsequently followed by
Melamed and Flehinger 188 for 3 years. In this sec-
ond study patients were matched for age, ethnic
origin, age at first pregnancy, number of children,
and net weekly family income before comparisons
were drawn in reference to their contraceptive use.
Incidence rates for precancerous cervical lesions
were estimated for three groups of women: dia-
16 HUGGINS AND GIUNTOLI
phragm users (1015 women), patients wearing an
intrauterine device (911 women), and patients
using oral contraceptives (5772 women). Each of
these patients had two normal cervical cytologic
examinations and returned for at least one annual
examination.
Each diaphragm user and each user of an in-
trauterine device (IUD) were matched with three
oral contraceptive users. Comparisons were made
between (1) oral contraceptive users and dia-
phragm users and (2) oral contraceptive users and
IUD users. The incidence rate of carcinoma in situ
or dysplasia for women using oral contraceptives
was not significantly different from that in
matched populations of women using a diaphragm
or an IUD.
Oryet al. 189 determined the prevalence rates for
cervical dysplasia and carcinoma in situ for 15,477
oral contraceptive users and 6,663 IUD users at
the Grady Hospital Family Planning Clinic in At-
lanta, Ga. This study was designed in part to an-
swer the question raised by the study by Melamed
et al., 171 namely, does the prevalence rate of cervi-
cal premalignant changes vary according to which
contraceptive method is initially accepted by
women entering a family planning program? The
IUD and oral contraceptive acceptors showed simi-
lar characteristics: all were black, age 15 to 44, and
had lower-middle class incomes. Marital status,
age at first pregnancy, and number of pregnancies
were similar. For 5164 women with 2 or more
Papanicolaou smears choosing the IUD, the crude
dysplasia rate was 1.3/100 women. Among 9431
similar oral contraceptive choosers the dysplasia
rate was 2.3/100 women. The calculated risk ratio
of 1.5 in this series was considered statistically
significant. Oral contraceptive acceptors with
Papanicolaou smears prior to initial choice of con-
traceptive method had a l.4-fold higher preva-
lence rate of cervical dysplasia than IUD ac-
ceptors. For these same groups of women with 2
smears the crude prevalence rate of carcinoma in
situ was 1.311100 women for IUD choosers and
0.34/100 women for oral contraceptive choosers.
These differences were not significant.
The group of women studied by Ory et al. 189 was
dissimilar to the group of women studied by
Melamed et al. 171 The patients in the series of
Melamed et al. were older, of higher parity, and
fewer were black. Another crucial difference was
that in their 1969 study Melamed et al. compared
only oral contraceptive and diaphragm users,
while Ory et al. compared oral contrceptive and
IUD users. Subsequently, Ory 190 conducted a
July 1979
case-control study of 584 women with cervical
dysplasia and 148 women with cervical carcinoma
in situ, comparing oral contraceptive versus IUD
use. These patients were taken from the same
population at Grady Hospital. None of the women
with dysplasia and carcinoma in situ had prior
abnormal smears, and all had at least two normal
smears prior to entry into the study. Lesions de-
veloped over a 2-year period of observation. Diag-
noses of abnormal smears were confirmed by cervi-
cal biopsies. Controls included 8553 black women
matched for age, educational status, marital
status, age at first birth, and parity. The control
patients had no prior abnormal smears and con-
tinued to have normal smears for the 2-year period
of the study. Analysis showed a "weak" association
between oral contraceptive use and dysplasia. The
relative risk of carcinoma in situ for oral con-
traceptive users as compared with nonusers rose
linearly from 1.3 (1 to 12 months' use) to 4.7 (>36
months' use). This trend was statistically
significant.
Cohort Studies of Cervical Neoplasia
Vessey et al. 32 found no cases of cervical
dysplasia among 4217 diaphragm users. The inci-
dences of dysplasia among 3162 IUD users and
9653 oral contraceptive users were similar (0.28
and 0.3111000 woman-years, respectively, with
only 12 cases recorded). No valid statistical
analysis was possible with so few cases.
The Royal College of General Practitioners3o re-
ported on only "malignant neoplasm of cervix
uteri." Two cases were observed in oral contracep-
tive takers, two cases among "ex-takers," and four
cases among the non-oral contraceptive takers.
These numbers were too small for statistical
analysis.
The Walnut Creek Study 33 involving 17,942
women observed for 37,373 woman-years initially
reported a statistically significant association be-
tween carcinoma in situ and duration of oral con-
traceptive use. This analysis involved only 34
cases of carcinoma in situ and did not include
analysis of age at first birth or sexual activity and
number of sexual partners; it showed a weaker
association which lost its statistical significance. 34
Stern et al. 191 reported a prospective study of 300
women with cervical dysplasia matched with 300
women with normal cervical smears. These pa-
tients were obtained from among 6000 women en-
rolled in a family planning clinic in Los Angeles,
Calif. The combined oral contraceptive chosen for
Vol. 32, No.1 ORAL CONTRACEPTIVES AND NEOPLASIA
the study contained 100 fLg of mestranol and 1 mg
of ethynodiol diacetate. Over 90% of the non-pill
users chose an intrauterine device.
The patients with dysplasia and their controls
were followed with a Papanicolaou smear every 6
months. Total study period for observation was 7
years. In the sample of women with normal smears
there was no evidence of a differential effect of the
pill. The patients with dysplasia taking oral con-
traceptives (compared with nonusers) showed a
significantly increased conversion of dysplasia to
carcinoma in situ with extended use (over 6 years).
Analysis was conducted using the life-table
method and involved only 32 patients with more
than 6 years' use. There was no suggestion of con-
version from dysplasia to carcinoma in situ for use
less than 6 years.
At present, it would appear that combined oral
contraceptives containing 50 fLg of estrogen and 1
mg of progestogen or less, used in low-risk popula-
tions, offer no significant risks for conversion from
normal cervical epithelium to dysplasia or car-
cinoma in situ. High-risk populations (those pa-
tients with early sexual activity, multiple part-
ners, high parity, or existent cervical dysplasia)
taking combined oral contraceptives containing
more than 50 fLg of estrogen and 1 mg ofprogesto-
gen for a prolonged time may be at increased risk
for progression from normal tissue to dysplasia to
carcinoma in situ. There are no firm data to
suggest an increased risk of progression to inva-
sive carcinoma of the cervix.
OVARIAN NEOPLASMS
Several studies have reported a lower incidence
of functional ovarian cysts in oral contraceptive
users versus nonusers.192-194 The cohort studies by
Vessey et aP2 and Ory et aP1 reported no associa-
tion between benign ovarian neoplasms and oral
contraceptive use. The Royal College cohort
studflO showed a decreased incidence of ovarian
tumors in oral contraceptive users; however, func-
tional cysts and true neoplastic lesions were not
analyzed separately.
OVARIAN CANCER
Few epidemiologic studies are available report-
ing ovarian cancer and oral contraceptive
use. 194 ,195 The data presented are reassuring (al-
though incomplete), demonstrating no increased
incidence and no association between ovarian
cancer and oral contraceptive use. Newhouse et
17
al.,195 in a case-comparison study of 300 women
with ovarian cancer, suggested that oral con-
traceptive use might protect against ovarian
cancer. These findings require confirmation from
other diversified patient populations.
CHORIOCARCINOMA
After initial evacuation of the hydatidiform
mole, urine levels of human chorionic gonadotro-
pin (HCG) fall rapidly, indicating absence offunc-
tioning trophoblastic tissue. These titers should be
negative within 2 weeks to several months after
evacuation. Persistence of elevated HCG titers or a
rising titer indicates persistent, functioning,
trophoblastic tissue and may signal malignant
change to choriocarcinoma. This change may take
place in 2% to 10% of untreated patients. 195 Con-
traception is most important during the early
months following treatment of hydatidiform mole.
A pregnancy will produce HCG and confound at-
tempts to detect persistent or recurrent disease.
Because of the need for reliance on HCG assays,
patients are advised not to establish a new preg-
nancy for the 1st year offollow-up c.fter treatment
of hydatidiform mole.
Stone et al. 196 investigated the influence of oral
contraceptive therapy on the course of surgically
treated hydatidiform moles. They found the need
for chemotherapy for trophoblastic tumor after
evacuation of a hydatidiform was significantly in-
creased in patients taking oral contraceptives be-
fore normal HCG values were obtained. Oral con-
traception was also found to delay the decrease in
HCG excretion in patients not requiring treat-
ment with cytotoxic drugs (Table 11). Until this
study can be confirmed or challenged, oral con-
traceptives should not be used in patients with
positive HCG titers who have been treated for
hydatidiform mole.
SUMMARY
Combined oral contraceptives have been used by
millions of women in the United States for almost
20 years. During this time, the steroid content of
these pills has been reduced markedly from their
high initial levels. All of the new formulations
introduced in the last 9 years contain less than 50
fLg of ethinylestradiol and less than 1 mg of
norethindrone. In the United States, because of
the suspected association with neoplasia in ani-
mals, the 17-hydroxyprogesterones are not in use.
Reports of an association between sequential oral
18 HUGGINS AND GIUNTOLI
TABLE 11. Relationship of Oral Contraceptives (OC) to
Development of Tumor Requiring Chemotherapy l96
Patients requiring
All treatment with
patients cytotoxic drugs
No.
Patients not taking OC at any 464 43
time
Patients taking OC before 65 16
HCGnormal
Patients taking OC when 26 0 0
HCGnormal
All patients 555 59
contraceptives and endometrial carcinoma have
contributed to withdrawal of the sequential formu-
lations from the United States market.
The problems in investigating neoplasia and
oral contraceptives include the following: (1) ab-
sence of a suitable animal model, (2) long lag-time
from exposure to development of disease, (3) low
incidence of specific neoplastic diseases, and (4)
multiple etiologic factors in the study population.
The principal investigative methods in the
human are various epidemiologic approaches. The
methodologies most frequently used are (1) case
reports (tumor registries), (2) disease rates and
trends, (3) case-comparison (retrospective)
studies, and (4) cohort (prospective) studies. These
methods cannot prove a causal relationship be-
tween exposure to a possible carcinogen and the
occurrence of disease. Care must be taken not to
extrapolate epidemiologic conclusions to dissimi-
lar populations. Consistent evidence (positive or
negative), confirmed by multiple epidemiologic
approaches, can be used to guide physicians and
regulatory agencies in formulating policy for the
clinical use of oral contraceptives.
Breast Disease
Both the progestogen-only and the combined
oral contraceptives have been shown to have a
protective effect on the development of benign
breast disease. This protective effect does not ap-
pear until 2 years of use. Data at present are in-
adequate to predict persistence beyond 4 years of
use. The protective effect appears to be due to the
progestogen component.
There may be at least two types of benign breast
disease, one of which is premalignant and the
other is not. The oral contraceptives appear to pro-
tect only against those benign lesions which are
not premalignant, with few exceptions.
Current epidemiologic data show no association
July 1979
(either adverse or beneficial) between oral con-
traceptive use and the development of carcinoma
of the breast in women.
There is need to better define patients at high
% risk for breast cancer and conduct appropriate
9.3 studies on these sUbpopulations.
24.6
Liver Tumors
Long-term combined oral contraceptive use ap-
pears to be related to the development of benign
11.2
liver neoplasia. The risk increases with the dose of
the steroid and the age of the user. These lesions
are quite rare (1 to 5/1,000,000 women). They may
be life-threatening because of potential spontane-
ous rupture and hemorrhage. The potential for
rupture appears to be related to the histologic type
of adenoma rather focal nodular hyperplasia.
Standard blood liver function tests are of little
value for screening diagnostic purposes. Physical
examination, ultrasound, angiography, and liver
scan are the most useful techniques for diagnosis.
Biopsy and resection are attendant with signifi-
cant risk of hemorrhage. There is some evidence
that these lesions will spontaneously regress fol-
lowing discontinuation of the oral contraceptive.
Pregnancy and resumption of use may exacerbate
these lesions.
Endometrial Hyperplasia
Long-term postmenopausal use of estrogens ap-
pears to increase significantly the risk of develop-
ing endometrial hyperplasia and adenocarcinoma
of the endometrium. Sequential oral contracep-
tives (14 to 16 days of high-dose, unopposed estro-
gen followed by estrogen-progestogen for 5 or 6
days) were withdrawn from use in the United
States in 1976. This action was in response to a few
case reports of endometrial hyperplasia and
adenocarcinoma occurring in young women taking
these formulations. There is no suggestion that the
use of combined oral contraceptives or
progestogen-only pills may be associated with the
development of endometrial hyperplasia or
adenocarcinoma of the endometrium.
Leiomyomas
Estrogens appear to be related to the growth of
pre-existing uterine leiomyomas. The use· of low-
dose combined oral contraceptives does not appear
to increase significantly the risk of developing or
increasing the growth of pre-existing leiomyomas.
 ORAL CONTRACEPI'IVES AND NEOPLASIA
Vol. 32, No.1
Cervical Changes
Endocervical cells under the influence ofproges-
togens may develop adenomatous changes. Al-
though benign, these changes have on occasion
been misinterpreted as carcinoma. Analysis ofthe
association between oral contraceptives and cervi-
cal neoplasia is especially difficult. The most im-
portant risk factors (age at first intercourse and
number of sexual partners) are difficult to deter-
mine accurately. Most studies conducted prior to
1975 did not consider these factors. In several
studies in which the data have been reanalyzed to
take these factors into account, the conclusions
have been altered.
There appears to be no increased risk of develop-
ing cervical dysplasia or carcinoma in situ for
low-risk populations of patients who use low-dose
combined oral contraceptives. High-risk patients
(early sexual activity, multiple partners, high par-
ity, patients with existent cervical dysplasia) tak-
ing combined oral contraceptives containing more
than 50 ILg of estrogen and 1 mg of progestogen for
a prolonged period of time may be at increased risk
for development of dysplasia or progression to car-
cinoma in situ. There are no firm data to suggest
an increased risk of progression of such lesions to
invasive carcinoma of the cervix.
Pituitary Neoplasia
The use of radioimmunoassay for prolactin and
poly tomography of the pituitary sella has mar-
kedly increased the ability to diagnose small
pituitary tumors. At present, data are insufficient
to establish any association between oral con-
traceptive use and pituitary neoplasia.
Choriocarcinoma
Oral contraceptives may have an adverse asso-
ciation with resolution of hydatidiform mole. Pa-
tients should not use steroidal contraception until
HeG titers are negative.
Acknowledgments. We are grateful to Joby Jackson, Sharon
Ricciarrdi, and Elizabeth Iannuzzi for their valuable technical
assistance and typing in preparation of the manuscript.
REFERENCES
1. Population Reports: Oral contraceptives: update on
usage, safety, and side effects. Baltimore, Population In-
formation Program, Johns Hopkins University, 1979, p
133
2. Peel J, Potts M: Oral contraceptives. In Textbook of Con-
traceptive Practice. Cambridge, England, Cambridge
University Press, 1970, p 95
19
3. Hatcher RA, Stewart GK, Stewart FS, Guest F, Stratton
P, Wright AH: Contraceptive Technology. New York, Ir-
vington Publishers Inc, 1978, p 41
4. Finkel MJ, Berliner VR: The extrapolation of experimen-
tal findings (animal to man): the dilemma of the systemi-
cally administered contraceptives. Bull Soc Pharmacol
Environ Pathol 4:13, 1973
5. Tietze C, Bongaarts J, Schearen B: Mortality associated
with the control offertility. Fam Plann Perspect 8:6,1976
6. Population Reports: Debate on oral contraceptives and
neoplasia continues; answers remain elusive.
Washington DC, George Washington University Medical
Center, 1977, p 78, Ser A4
7. Population Reports: U.S. morbidity and mortality trends
relative to oral contraceptive use 195&-1975. Washington
DC, George Washington University Medical Center,
1977, pAl, Ser A4 [Suppl]
8. Hueper WC: Environmental cancer. In The
Physiopathology of Cancer, Second Edition, Edited by F
Homburger. New York, Hoeber, 1959, p 919
9. Committee on Safety of Medicines: Carcinogenicity Tests
of Oral Contraceptives. London, Her Majesty's Stationery
Office, 1972, p 23
10. Drill VA: Experimental and clinical studies on relation-
ship of estrogens and oral contraceptives to breast cancer.
In Experimental Model Systems in Toxicology and Their
Significance in Man, Edited by WAM Duncan. Proceed-
ings of the European Society for the Study of Drug Toxic-
ity, Vol 15, Zurich, Switzerland, 1973. Amsterdam, Ex-
cerpta Medica Int Congr Ser 311, 1974, P 200
11. Rudali G, Coezy E, Chemama R: Mammary car-
cinogenesis in female and male mice receiving contracep-
tives or gestagens. J Natl Cancer Inst 49:813, 1972
12. Bern HA, Nandi S: Recent studies of the hormonal
influence in mouse mammary tumorigenesis. In Progress
in Experimental Tumor Research, Vol 2, Edited by F
Homburger. New Yor k, Hafner Publishing Co, 1961, P 91
13. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma
of the vagina: association of maternal stilbestrol therapy
with tumor appearance in young women. N Engl J Med
284:878, 1971
14. Baum JK, Holtz F, Bookstein JJ, Klein EW: Possible
association between benign hepatomas and oral con-
traceptives. Lancet 2:926, 1973
15. Waterhouse J, Muir C, Correa P, Powell J (Editors):
Cancer Incidence in Five Continents, Vol 3. Lyon, France,
International Agency for Research on Cancer (IARC Sci-
entific Publication No 15), 1976, 586 P
16. Seidman H, Sibberberg E, Holley A: Cancer statistics
1976: a comparison of white and black populations. CA
26:9,1976
17. Paffenbarger RS Jr, Fasal E, Simmons ME, Kampert JB:
Cancer risk as related to use of oral contraceptives during
fertile years. Cancer 39:1887, 1977
18. Silverberg E: Gynecologic cancer: statistical and
epidemiological information. American Cancer Society
Professional Educational Publication, 1975, p 16
19. Cramer DW, Cutler SJ, Cristine W: Trends in the inci-
dence of endometrial cancer in the U.S. Gynecol Oncol
2:130,1974
20. Third National Cancer Survey: Incidence Data of the Na-
tional Cancer Institute Monogr No 41, DHEW Publica-
tion No (NIH)75-787, Edited by SJ Cutler, SL Young.
Washington DC, United States Government Printing
Office, 1975
20 HUGGINS AND GIUNTOLI
21. Cramer DW, Cutler SJ: Incidence and histopathology of
malignancies of the female genital organs in the US. AmJ
Obstet GynecoI118:443, 1974
22. Cornfield J, Haenszel W: Some aspects of retrospective
studies. J Chronic Dis 11(5):523, 1960
23. Doll R, Vessey MP: Evaluation of rare adverse effects of
systemic contraceptives. Br Med Bull 26:33, 1970
24. Dorn HF: Some problems arising in prospective and re-
trospective studies of the etiology of disease. N Engl J Med
261:571, 1959
25. Hardy RJ, White C: Matching in retrospective studies.
Am J Epidemiol 93:75, 1971
26. MacMahon B, Pugh TF: Epidemiology: Principles and
Methods. Boston, Little, Brown and Co, 1970, 376 p
27. Sartwell PE: Retrospective studies: a review for the clini-
cian. Ann Intern Med 81:381, 1974
28. Schlesselman JJ: Sample size requirements in cohort and
case-control studies of disease. Am J Epidemiol 99:381,
1974
29. Seigel D, Corfman P: Epidemiological problems associ-
ated with studies of the safety of oral contraceptives.
JAMA 203:148, 1968
30. Royal College of General Practitioners: Oral Contracep-
tivesandHealth.NewYork,PitmanPublishingCo, 1974
31. Ory H, Cole P, MacMahon B, Hoover R: Oral contracep-
tives and reduced risk of benign breast disease. N Engl J
Med 294:419, 1976
32. Vessey MP, Doll R, Peto R, Johnson B, Wiggins P: A
long-term follow-up study of women using different
methods of contraception: an interim report. J Biosoc Sci
8:375,1976
33. Ramcharan S: The Walnut Creek Contraceptive Drug
Study, A Prospective Study of the Side-Effects of Oral
Contraceptives, Vol 1, DHEW Publication No (NIH).
Washington DC, United States Government Printing
Office, 1974
34. World Health Organization Technical Report Series:
Steroid Contraception and the Risk of Neoplasia, No 619,
1978
35. Leis HP: Epidemiology of breast cancer: identification of
the high-risk woman. In The Breast, Edited by HS Gal-
lagher, HP Leis, RK Snyderman, JA Urban. Saint Louis
Mo, CV Mosby Co 1978, p 38
36. Leis HP, Black MM, SaIl S: The pill and the breast. J
Reprod Med 16:5, 1976
37. Holleb AI, Freeman HP, Farrow JH: Cancer of the male
breast. NY State J Med 68:544, 1968
38. Symmers W St C: Carcinoma of breast in trans-sexual
individuals after surgical and hormonal interference with
the primary and secondary sex characteristics. Br J Med
2:83,1968
39. Hoover R, Gray LA, Cole P, MacMahon B: Menopausal
estrogens and breast cancer. N Engl J Med 295:401,1976
40. Petrakis NL: Genetic factors in the etiology of breast
cancer. Cancer 39:2709, 1977 . 67. Lacassagne A: Apparition de cancers de la mamelle chez
41. Anderson DE: Some characteristics of familial breast
cancer. Cancer 28:1500, 1971
42. Anderson DE: Genetic study of breast cancer: identifica-
tion of a high risk group. Cancer 34:1090, 1974
43. Petrakis NL: Cerumen genetics and human breast
cancer. Science 173:347, 1971
44. Warren S: The relation of "chronic mastitis" to carcinoma
of the breast. Surg Gynecol Obstet 71:257, 1940
45. Monson RR, Yen S, MacMahon B: Chronic mastitis and
carcinoma of the breast. Lancet 2:224, 1976
July 1979
46. Donnelly PK, Baker KW,.Carney JA, O'Fallon WM: Be-
nign breast lesions and subsequent breast carcinoma in
Rochester, Minnesota. Mayo Clin Proc 50:650,1975
47. Davis HH, Simons M, Davis JB: Cystic disease of the
breast: relationship to carcinoma. Cancer 17:957, 1964
48. Black MM, Barclay THC, Cutler SJ, Hankey BF, Asire
AJ: Association of atypical characteristics of benign
breast lesions with subsequent risk of breast cancer.
Cancer 29:338, 1972
49. Copeland MM: Precancerous lesions ofthe breast: how to
treat them. Postgrad Med 27:332, 1960
50. Potter JF, Slimbaugh WP, Woodward SC: Can breast
carcinoma be anticipated? A follow-up of benign breast
biopsies. Ann Surg 167:829, 1968
51. Nomura A, Comstock GW, Tomascia JA: Epidemiologic
characteristics of benign breast disease. Am J Epidemiol
105:505, 1977
52. Gullino PM: Natural history of breast cancer progression
from hyperplasia to neoplasia as predicted by an-
giogenesis. Cancer 39:2697, 1977
53. Spratt JS Jr, Spratt TL: Rates of growth of pulmonary
metastases and host survival. Ann Surg 159:161, 1964
54. Collins VP, Loefller RK, Tivey H: Observations on growth
rates of human tumors. Am J Roentgenol Radium Ther
Nucl Med 76:988, 1956
5. Silvestrimi R, Sanfilippo 0, Tedesco G: Kinetics of human
mammary carcinomas and their correlation with the
cancer and the host characteristics. Cancer 34: 1252, 1974
56. Kodlin D, Winger EE, Morgenstern NL, Chen V: Chronic
mastopathy and breast cancer. Cancer 39:2603,1977
57. McDivitt RW, Hutter RV, Foote FW, Stewart FW: In situ
lobular carcinoma, a prospective follow-up study indicat-
ing cumulative patient risks. JAMA 201:96, 1967
58. Black MM, Chabon AB: In situ carcinoma of the breast.
Pathol Annu 4:185,1969
59. Shapiro S, Strax P, Venet L, Fink R: The search for risk
factors in breast cancer. AmJ Public Health 58:820,1968
60. Zippin CC, Petrakis NL: Identification of high risk groups
in breast cancer. Cancer 28:1381, 1971
61. Cole PT: Oral contraceptives and breast neoplasia.
Cancer 39: 1906, 1977
62. Feinleib M: Breast cancer and artificial menopause: a
cohort study. J Natl Cancer Inst 41:315, 1968
63. Hirayama T, Wynder EL: A study of the epidemiology of
cancer of the breast: the influence of hysterectomy.
Cancer 15:28, 1962
64. Lilienfeld AM: The relationship of cancer of the female
breast to artificial menopause and marital status. Cancer
9:927, 1956
65. Trichopoulos D, MacMahon B, Cole P: Menopause and
breast cancer risk. J Natl Cancer Inst 48:605, 1972
66. Stoll BA: Hypothesis: breast cancer regression under oes-
trogen therapy. Br Med J 3:446, 1973
la souris male, soumise a des injections de folliculine [the
appearance of mammary cancer in male mice by injection
of folliculine (FR)]. CR Acad Sci 195:630, 1932
68. Huggins C, Yang NC: Induction and extinction of mam-
mary cancer. Science 137:257, 1962
69. Kirschner MA: The role of hormones in the etiology of
human breast cancer. Cancer 39:2716, 1977
70. Lemon HM, Wotiz HH, Parsons L, Mozden PJ: Reduced
estriol excretion in patients with breast cancer prior to
endocrine therapy. JAMA 196:112, 1966
 ORAL CONTRACEPTIVES AND NEOPLASIA
Vol. 32, No.1
71. Cole P, MacMahon B: Oestrogen fractions during early
reproductive life in the aetiology of breast cancer. Lancet
1:604,1969
72. Brecher PI, Wotiz HH: Competition between estradiol
and estriol for end organ receptor proteins. Steroids 9:431,
1967
73. Lemon HM: Endocrine influences on human mammary
formation: a critique. Cancer 23:781, 1969
74. MacMahon B, Cole P, Brown JB, Aoki K, Lin TM, Morgan
RW, Woo NC: Oestrogen profiles of Asian and North
American women. Lancet 2:900,1971
75. Dickinson LE, MacMahon B, Cole P, Brown JB: Estrogen
profiles or Oriental and Caucasion women in Hawaii. N
Engl J Med 291:1211, 1974
76. Leis HP: Hormones in the epidemiology of breast cancer.
Dis Breast 2:7, 1976
77. Brenner PF, Mishell DR, Stanczyk FZ, Goebelsmann U:
Serum levels of d-norgestrel, luteinizing hormone,
follicle-stimulating hormone, estradiol, and progesterone
in women during and following ingestion of combination
oral contraceptives containing dl-norgestrel. Am J Obstet
Gynecol 129: 133, 1977
78. Hellman L, Zumoff B, Fishman J, Gallagher TF:
Peripheral metabolism of 3H-estradiol and the excretion
of endogenous estrone and estriol glucosiduronate in
women with breast cancer. J Clin Endocrinol Metab
33:138,1971
79. Marmorston J, Crowley LG, Myers SM, Stern E, Hopkins
CE: Urinary excretion of estrone, estradiol and estriol by
patients with breast cancer and benign breast disease.
Am J Obstet Gynecol 92:460, 1965
80. Papaioannou AN: Etiologic factors in cancer of the breast
in humans. Surg Gynecol Obstet 138:257, 1974
81. Deshpande N, Carson P, Horner J: Oestriol in human
breast tumors. J Steroid Biochem 7:11, 1976
82. Flood C, Pratt JH, Longcope C: The metabolic clearance
and blood production rates of estriol in normal, non-
pregnant women. J Clin Endocrinol Metab 42:1, 1976
83. Longcope C, Pratt JH: Breast cancer and estriol
dynamics. Program of the Breast Cancer Task Force, Di-
vision of Cancer Biology Diagnosis, NIH, San Antonio,
Texas, 1975, pp 62-63
84. Vessey MP, Doll R, Sutton PM: Oral contraceptives and
breast neoplasia: a retrospective study. Br Med J 3:719,
1972
85. Arthes FG, Sartwell PE, Lewison EF: The pill, estrogens
and the breast: epidemiologic aspects. Cancer 28:1391,
1971
86. Sartwell PE, Arthes FG, Tonascia JA: Epidemiology of
benign breast lesions: lack of association with oral con-
traceptive use. N Engl J Med 288:551, 1973
87. Fasal E, Paffenbarger RS Jr: Oral contraceptives as re-
lated to cancer and benign lesions of the breast. J Natl
Cancer Inst 55:767, 1975
88. Boston Collaborative Drug Surveillance Program: Oral
contraceptives and venous thromboembolic disease, sur-
gically confirmed gallbladder and breast tumours. Lancet
1:1400, 1973
89. Kelsey JL, Lindfors KK, White C: A case-control study of
the epidemiology of benign breast disease with reference
to oral contraceptive use. Int J Epidemiol 3:333, 1974
90. Kelsey JL, Holford TR, White C, Mayer ES, Kitty SE,
Acheson RM: Oral contraceptives and breast disease: an
epidemiological study. Am J Epidemiol107:236, 1978
21
91. Hoover R, Bain C, Cole P, MacMahon B: Oral contracep·
tive use association with frequency of hospitalization and
chronic disease risk indicators. Am J Public Health
68:335, 1978
92. Janerich DT, Glebatis DM, Dugan JM: Benign breast
disease and oral contraceptive use. JAMA 237:2199,1977
93. Nomura A, Comstock GW: Benign breast tumor and es-
trogen hormones: a population-based retrospective study.
Am J Epidemiol 103:439, 1976
94. Livosli VA, Stadel BV, Kelsey JL, Holford TR, White C:
Fibrocystic breast disease in oral contraceptive users: a
histopathological evaluation of epithelial atypia. N Engl
J Med 299:381, 1978
95. Spencer JD, Millis RR, Hayward JL: Contraceptive
steroids and breast cancer. Br Med J 1:1024, 1978
96. Horvath E, Kovacs K, Ross RC: Ultrastructural findings
in a well differentiated hepatoma. Digestion 7:74, 1972
97. Baum JK, Holtz F, Bookstein JJ, Klein EW: Possible
association between benign hepatomas and oral con-
traceptives. Lancet 2:926, 1973
98. Edmondson HA: Atlas of Tumor Pathology. Washington
DC, Armed Forces Institute of Pathology, 1958, Sect 7, p
18
99. Ameriks JA, Thompson NW, Frey CF, Appleman HD,
Walter JF: Hepatic cell adenomas, spontaneous liver rup-
ture and oral contraceptives. Arch Surg 110:548, 1975
100. Christopherson WM, Mays ET: Liver tumors and con-
traceptive steroids: experience with the first one hundred
registry patients. J Natl Cancer Inst 58:167, 1977
101. Mays ET, Christopherson WM, Barrows GH: Focal nodu-
lar hyperplasia of the liver: possible relationship to oral
contraceptives. Am J Clin Pathol 61:735, 1974
102. Mays ET, Christopherson WM, Mahr MM, Williams HC:
Hepatic changes in young women ingesting contraceptive
steroids: hepatic hemorrhage and primary hepatic
tumors. JAMA 235:730, 1976
103. McAvoy JM, Tompkins RJ, Longmire WI> Jr: Benign
hepatic tumors and their association with oral contracep-
tives: case reports and survey ofthe literature. Arch Surg
111:761, 1976
104. Nissen ED, Kent DR, Nissen SE: Etiology factors in the
pathogenesis of liver tumors associated with oral con-
traceptives. Am J Obstet Gynecol 127:61, 1977
105. Vana J, Murphy GP, Aronoff BL, Baker HW: Study of
association between liver tumors and oral contraceptive
use. Unpublished data, 1977
106. Keifer WS, Scott JC: Liver neoplasms and the oral con-
traceptives. Am J Obstet GynecoI128:448, 1977
107. Edmondson HA, Henderson B, Benton B: Liver-cell
adenomas associated with use of oral contraceptives. N
Engl J Med 294:470, 1976
108. Nissen ED, Kent DR, Nissen SE, McCrae DM: The associ-
ation of liver tumors with oral contraceptives. Obstet
Gynecol 48:49, 1976
109. Armed Forces Institute of Pathology, Hepatic Branch and
Center for Disease Control, Bureau of Epidemiology,
Family Planning Evaluation Division: Increased risk of
hepatocellualr adenoma in women with long-term use of
oral contraceptives. Morbidity Mortality Weekly Rep
26:293, 1977
110. Garcia CR, Gordon J, Drill VA: Contraceptive steroids
and liver lesions. J Toxicol Environ Health 3:197, 1977
111. Berg JW, Ketelaar RJ, Rose EF, Vernon RG: Hepatomas
and oral contraceptives. Lancet 2:349, 1974
22 HUGGINS AND GIUNTOLI
112. Vessey MP, Kay CR, Baldwin JA, Clarke JA, MacLeod
IE: Oral contraceptives and benign liver tumors. Br MedJ
1:1064, 1977
113. Edmondson HA, Reynolds TB, Henderson B, Benton B:
Regression of liver cell adenomas associated with oral
contraceptives. Ann Intern Med 86:180, 1977
114. Ramseur WL, Cooper MR: Asymptomatic liver cell
adenomas: another case of resolution after discontinua-
tion of oral contraceptive use. JAMA 239:1647, 1978
115. Anderson PH, Packer JT: Hepatic adenoma observations
after estrogen withdrawal. Arch Surg 111:898, 1976
116. Kent DR, Nissen ED, Nissen SE, Ziehm DJ: Effect of
pregnancy on liver tumor associated with oral contracep-
tives. Obstet Gynecol 51:148, 1978
117. Hibbard LT: Spontaneous rupture of the liver in preg-
nancy: a report of eight cases. Am J Obstet Gynecol
126:334, 1967
118. Kent DR, Nissen ED, Nissen SE, Chambers C: Maternal
death resulting from rupture of liver adenoma associated
with oral contraceptives. Obstet Gynecol 50:55, 1977
119. Baird IN, Hawley RG: Spontaneous rupture of the liver
during pregnancy. J Reprod Med 6:93, 1971
120. Knowles DM, Casarella WJ, Johnson PM, Wolff M: The
clinical, radiologic and pathologic characterization of be-
nign hepatic neoplasms: alleged association with oral
contraceptives. Medicine 57:223, 1978
121. Shearman RP: Amenorrhea after treatment with oral
contraceptives. Lancet 2:1110, 1966
122. Kleinberg DL, Noel GL, FrantzAG: Galactorrhea: a study
of235 cases, including 48 with pituitary tumors. N Engl J
Med 296:589, 1977
123. Chang RJ, Keye WR Jr, Young JR, Wilson CB, Jaffe RB:
Detection, evaluation, and treatment of pituitary micro-
adenomas in patients with galactorrhea and amenorrhea.
Am J Obstet Gynecol 128:356, 1977
124. Davajan V, Kletzky 0, March CM, Roy S, Mishell DR Jr:
The significance of galactorrhea in patients with normal
menses, oligomenorrhea, and secondary amenorrhea. Am
J Obstet Gynecol 130:894, 1978
125. Sherman BM, Harris CE, Schlechte J, Duello TM, Halmi
NS, Van Gilder J, Chapler FK, Granner DK: Pathogene-
sis of prolactin screening pituitary adenomas. Lancet
2:1019, 1978
126. March CM, Kletzky OA, Israel R, Davajan V, Mishell DR:
Amenorrhea, galactorrhea and piotuitary tumors: post-
pill and non-postpill. Fertil Steril 28:346, 1977
127. Van Campenhout J, Blanchet P, Hugues B, Papas S:
Amenorrhea following the use of oral contraceptives. Fer-
til Steril 28:728, 1977
128. March CM, Mishell DR, Kletzky OA, Israel R, Davajan V,
Nakamura RM: Galactorrhea and pituitary tumors in
postpill and non-postpill secondary amenorrhea (pitui-
tary tumors in secondary amenorrhea). Am J Obstet
Gynecol 134:45, 1979
129. Costello RT: Subclinical adenoma of the pituitary gland.
Am J Pathol 12:205, 1936
130. Coulam CB, Annegers JF, Abboud CF, Laws ER Jr, Kur-
land LT: Pituitary adenoma and oral contraceptives: a
case-control study. Fertil Steril 31:25, 1979
13l. Gusberg SB, Kaplan AL: Precursors of corpus cancer.
Adenomatous hyperplasia as stage 0 carcinoma of the
endometrium. Am J Obstet Gynecol 87:662, 1963
132. Gusberg SB, Moore DB, Martin F: Precursors of corpus
cancer. 2. A clinical and pathological study of adenoma-
tous hyperplasia. Am J Obstet Gynecol 68:1472, 1954
July 1979
133. Lucas WE: Causal relationships between endocrine-
metabolic variables in patients with endometrial car-
cinoma. Obstet Gynecol Survey 29:507,1974
134. Bromberg YM, Libane E, Laufera A: Early endometrial
carcinoma following prolonged estrogen administration
in an ovariectomized woman. Obstet Gynecol 14:221,
1959
135. Fremont-Smith M, Meigs JV, Gramham RM, Gilbert HH:
Cancer of endometrium and prolonged estrogen therapy.
JAMA 131:805, 1946
136. Sommers SC: Carcinoma of the endometrium. In The
Uterus, Edited NJ Norris, AT Hertig, MR Abell. Balti-
more, Williams & Wilkins Co, 1973, p 277
137. Gusberg SB, Kardon P: Proliferative endometrial re-
sponse to theca-granulosa cell tumors. Am J Obstet
Gynecol 111:633, 1971
138. Fechner RE, Kaufman RH: Endometrial adenocar-
cinoma. Cancer 34:444, 1974
139. Gusberg SB: Precursors of corpus carcinoma, estrogens,
and adenomatous hyperplasia. Am J Obstet Gynecol
54:905, 1947
140. Mack TM, Pike MC, Henderson BE, Pfeffer RI, Gerkins
VR, Aurthur M, Brown SE: Estrogens and endometrial
cancer in a retirement community. N Engl J Med
294: 1262, 1976
141. Gray LA, Christopherson WM, Hoover RN: Estrogens and
endometrial carcinoma. Obstet Gynecol 49:385, 1977
142. Smith DC, Prentice R, Thompson DJ, Herrmann WL:
Association of exogenous estrogen and endometrial car-
cinoma. N Engl J Med 293:1164, 1975
143. Zeil HK, Finkle WD: Increased risk of endometrial car-
cinoma among users of conjugated estrogens. N Engl J
Med 293:1167, 1975
144. McDonald TW, Annegers JF, O'Fallon WM, Dockerty
MB, Malkasian GD Jr, Kurkland LT: Exogenous estrogen
and endometrial carcinoma: case-control and incidence
study. Am J Obstet Gynecol 127:572, 1977
145. Antunes CMF, Stolley PD, Rosenshein NB, Davies JL,
Tonascia JA, Brown C, Burnett L, Rutledge A, Pokemp-
ner M, Garcia R: Endometrial cancer and estrogen use. N
Engl J Med 300:9, 1979
146. Garcia CR, Goldzieher JW, Massey JB: Oral contracep-
tives in human reproduction, conception and contracep-
tion, Edited by ESE Hafez, TN Evans. Hagerstown Md,
Harper and Row, 1973, p 335
147. Goldzieher JW, Martinez-Manatow J, Livingston NB,
Moses LE, Rice-Wray E: The use of sequestial estrogen
and progestin to inhibit fertility. West J Surg 71:187,
1963
148. Silverberg SG, Makowski EL: Endometrial carcinoma in
young women taking oral contraceptives. Obstet Gynecol
46:503, 1975
149. Lyon FA: The development of the endometrium in young
women receiving long-term sequential oral contracep-
tion: Report of four cases. Am J Obstet Gynecol 123:299,
1975
150. Silverberg SG, Makowski EL, Roche WD: Endometrial
carcinoma in women under 40 years of age: comparison of
cases in oral contraceptive users and non-users. Cancer
29:592, 1977
15l. Lyon FA, Frisch MJ: Endometrial abnormalities occur-
ring in young women on long-term sequential oral con-
traception. Obstet Gynecol 47:636, 1976
152. Cohen CJ, Deppe G: Endometrial carcinoma and oral
contraceptive agents. Obstet Gynecol 49:390, 1977
 ORAL CONTRACEPI'IVES AND NEOPLASIA
Vol. 32, No.1
153. Kelley HW, Miles PA, Buster JE, Scragg WH: Adenocar-
cinoma of the endometrium in women taking sequential
oral contraceptives. Obstet Gynecol 47:200, 1976
154. Kreutner A Jr, Johnson D, Williamson MO: Histology of
the endometrium in long-term use of a sequential oral
contraceptive. Fertil Steril 27:905, 1976
155. Anonymous: Sequential oral contraceptives removed
from the market. FDA Drug Bull 6:26, 1976
156. Tseng L, Gurpide E: Effect of estrone and progesterone on
the nuclear uptake of estradiol by slices of human en-
dometrium. Endocrinology 93:245, 1973
157. Tseng L, Gurpide E: Effects of progestins on estradiol
receptor levels in human endometrium. J Clin Endocrinol
Metab 41:402, 1975
158. Ravenholt RL: Malignant cellular evolution: an analysis
of the causation and prevention of cancer. Lancet 1:523,
1966
159. Kistner RW: The effects of progestational agents on
hyperplasia and carcinoma in situ of the endometrium: a
10 year follow-up. Int J Gynecol Obstet 8:561, 1970
160. Czernobilsky B, Garcia CR, Wallach EE: Endometrial
histology and parenteral estrogen-progestogen adminis-
tration. Fertil Steril 20:75, 1969
161. Flowers CE: Effects of new low dosage form of
norethynodrel-mestranol. Clinical evaluation and en-
dometrial biopsy study. JAMA 188:1115, 1964
162. Wentz WB: Progestin therapy in endometrial
hyperplasia. Gynecol Oncol 2:362, 1974
163. Kistner RW: The effects of progestational agents on
hyperplasia and carcinoma in situ of the endometrium.
Int J Obstet Gynecol 8:561, 1970
164. Ferenczy A: How progestogens effect endometrial
hyperplasia and neoplasia. Contemp Ob/Gyn 11:137,
1978
165. Green TH: Leiomyomas, adenomyosis and other benign
diseases ofthe uterus. In Gynecology: Essentials ofClini-
cal Practice, Third Edition. Boston, Little, Brown and Co,
1977, p 381
166. Martin CE: Marital and coital factors in cervical cancer.
Am J Public Health 57:803, 1967
167. Rotkin ID: A comparison review of key epidemiological
studies in cervical cancer related to current searches for
transmissible agents. Cancer Res 33:1353, 1973
168. Merritt CG, Rosenberg SH, Edington B, Losciuto LA: Age
at first coitus and choice of contraceptive method: pre-
liminary report on a study of factors related to cervical
neoplasia. Soc BioI 22:255, 1975
169. Miller DF: The impact of hormonal contraceptive therapy
on a community and effects on cytopathology of the cervix.
Am J Obstet Gynecol 115:978, 1973
170. Worth AJ, Boyes DA: A case control study into the possi-
ble effects of birth control pills on pre-clinical carcinoma
of the cervix. J Obstet Gynaecol Br Commonw 79:673,
1972
171. Melamed MR, Koss LG, Flehinger BJ, Kelisky RP, Dub-
row H: Prevalence rates of uterine cervical carcinoma in
situ for women using the diaphragm or contraceptive oral
steroids. Br Med J 3:195, 1969
172. Amstey MS: Genital herpes virus and cervical carcinoma.
Con temp Ob/Gyn 3:99, 1977
173. Adelvsi B, Osunkoya BO, Fabiyi A: Herpes type-2 virus
antigens in human cervical carcinoma. Obstet Gynecol
47:545, 1976
174. Tobin SM, Wilson WD, Papsin FR: Relation of herpes
Received April 3, 1979.
Reprint requests: George R. Huggins, M.D., Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania,
3400 Spruce Street, Philadelphia, Pa. 19104.
23
virus hominis type II to carcinoma of the cervix. Obstet
Gynecol 51:707, 1978
175. Gall SA, Bourgeois CH, Maguire R: The morphological
effects of oral contraceptive agents on the cervix. JAMA
207:2243, 1969
176. Wilkinson E, Dufour DR: Pathogenesis of microglandular
hyperplasia of the cervix uteri. Obstet Gynecol 47:189,
1976
177. Coppelson M, Reid B: A colposcopic study of the cervix
during pregnancy and the puerperium. J Obstet Gynaecol
Br Commonw 73:575, 1966
178. Fluhmann CF: Histology. In The Cervix Uteri and Its
Diseases, Edited by CF Fluhmann. Philadelphia, WB
Saunders Co, 1961, p 46
179. Coppelson M, Reid B: Origin of premalignant lesions of
cervix uteri. Prog Gynecol 6:517, 1975
180. Candy J, Abell MR: Progestogen-induced adenomatous
hyperplasia of the uterine cervix. JAMA 203:85, 1968
181. Payan HM: Atypical endocervical hyperplasia and oral
contraceptives: report of a case. Michigan Med 70:609,
1971
182. Graham J, Graham R, Hirabayashi K: Reversible
"cancer" and the contraceptive pill. Obstet Gynecol
31:190, 1968
183. Anderson WR, Levine AJ: The contraceptive polyp: a
diagnostic dilemma. J Iowa Med Soc 58:585, 1968
184. Taylor HB, Irey NS, Norris HJ: Atypical endocervical
hyperplasia in women taking oral contraceptives. JAMA
202:185, 1967
185. Thomas DB: Relationship of oral contraceptives to cervi-
cal carcinogenesis. Obstet Gynecol 40:508, 1972
186. Miller DF: The impact of hormonal contraceptive therapy
on a community and effects on cytopathology ofthe cervix.
Am J Obstet Gynecol 115:978, 1973
187. Boyce JG, Lu T, Nelson JH, Furchter RG: Oral contracep-
tives and cervical carcinoma. Am J Obstet Gynecol
128:761, 1977
188. Malamed MR, Flehinger BJ: Early incidence rates of pre-
cancerous cervical lesions in women using oral contracep-
tives. Gynecol Oncol 1:290, 1973
189. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW: Con-
traceptive choice and prevalence of cervical dysplasia and
carcinoma in situ. Am J Obstet Gynecol 124:573, 1976
190. Ory HW, Conger SB, Naib Z, Tyler CW, Hatcher RA:
Preliminary analysis of oral contraceptive use and risk of
developing premalignant lesions of the uterine cervix. In
Pharmacology of Steroid Drugs, Edited by S Garrantini,
HW Berendes. New York, Raven Press, 1977
191. Stern E, Forsythe AB, Coffelt CF: Steroid contraceptive
use and cervical dysplasia; increased risk of progression.
Science 196:1460, 1977
192. Ory H: Functional ovarian cysts and oral contraceptives:
negative association confirmed surgically: a cooperative
study. JAMA 228:68, 1974
193. Ylukorkala 0: Ovarian cysts and hormonal contracep-
tion. Lancet 2:1101, 1977
194. Lingeman CH: Etiology of cancer of the human ovary, a
review. J Natl Cancer Inst 53:1603, 1974
195. Newhouse ML, Pearson RM, Fullerton JM, Boesen EAM,
Shannon HS: A case control study of carcinoma of the
ovary. Br J Preventive Soc Med 31:148, 1977
196. Stone M, Dent J, Kardana A, Bagshawe KD: Relationship
of oral contraception to the development of trophoblastic
tumour after evacuation of a hydatidiform mole. Br J
Obstet Gynaecol 83:913, 1976